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Complexity of the cell's transport and communication system

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Complexity of the cell's transport and communication system

http://reasonandscience.heavenforum.org/t2118-complexity-of-the-cell-s-transport-and-communication-system



Eukaryotic cells contain intracellular membrane-enclosed organelles that make up nearly half the cell’s total volume. The main ones present in all eukaryotic cells are the endoplasmic reticulum, Golgi apparatus, nucleus, mitochondria, lysosomes, endosomes, and peroxisomes; plant cells also contain plastids such as chloroplasts. These organelles contain distinct sets of proteins, which mediate each organelle’s unique function. Each newly synthesized organelle protein must find its way from a ribosome in the cytosol, where the protein is made, to the organelle where it functions. It does so by following a specific pathway, guided by sorting signals in its amino acid sequence that function as either signal sequences or signal patches. Sorting signals are recognized by complementary sorting receptors, which deliver the protein to the appropriate target organelle. Proteins that function in the cytosol do not contain sorting signals and therefore remain there after they are synthesized. During cell division, organelles such as the ER and mitochondria are distributed to each daughter cell. These organelles contain information that is required for their construction, and so they cannot be made de novo.

Nuclear transport 2

The entry and exit of large molecules from the nucleus is tightly controlled by the nuclear pore complexes. Although small molecules can enter the nucleus without regulation,macromolecules such as RNA and proteins require association karyopherins called importins to enter the nucleus and exportins to exit. "Cargo" proteins that must be translocated from the cytoplasm to the nucleus contain short amino acid sequences known as nuclear localization signals, which are bound by importins, while those transported from the nucleus to the cytoplasm carry nuclear export signals bound by exportins. The ability of importins and exportins to transport their cargo is regulated by GTPases, enzymes that hydrolyze the molecule guanosine triphosphate to release energy. The key GTPase in nuclear transport is Ran, which can bind either GTP or GDP (guanosine diphosphate), depending on whether it is located in the nucleus or the cytoplasm. Whereas importins depend on RanGTP to dissociate from their cargo, exportins require RanGTP in order to bind to their cargo.

Nuclear import depends on the importin binding its cargo in the cytoplasm and carrying it through the nuclear pore into the nucleus. Inside the nucleus, RanGTP acts to separate the cargo from the importin, allowing the importin to exit the nucleus and be reused. Nuclear export is similar, as the exportin binds the cargo inside the nucleus in a process facilitated by RanGTP, exits through the nuclear pore, and separates from its cargo in the cytoplasm. Specialized export proteins exist for translocation of mature mRNA and tRNA to the cytoplasm after post-transcriptional modification is complete. This quality-control mechanism is important due to these molecules' central role in protein translation; mis-expression of a protein due to incomplete excision of exons or mis-incorporation of amino acids could have negative consequences for the cell; thus, incompletely modified RNA that reaches the cytoplasm is degraded rather than used in translation.

Components of Coated Vesicles and Nuclear Pore Complexes Share a Common Molecular Architecture 1
To date three major kinds of transport vesicles, distinguished by the compositions of their protein coat complexes, have been shown to traffic between these internal membranes and the plasma membrane:

First, theclathrin/adaptin complexes are responsible for endocytosis and vesicular trafficking between the Golgi, lysosomes, and endosomes;
second, the COPI complex mediates intra-Golgi and Golgi-to-ER trafficking;
and lastly, the COPII complex supports vesicle movement from the ER to the Golgi

Mature Eukaryotic mRNAs Are Selectively Exported from the Nucleus
Eukaryotic pre-mRNA synthesis and processing take place in an orderly fashion within the cell nucleus. But of the pre-mRNA that is synthesized inside the nucleus of the cell by RNA polymerase, only a small fraction— the mature mRNA—is of further use to the cell. Most of the rest—excised introns, broken RNAs, and aberrantly processed pre-mRNAs—is not only useless but potentially dangerous. How does the cell distinguish between the relatively rare mature mRNA molecules it wishes to keep and the overwhelming amount of debris created by RNA processing? The answer is that, as an RNA molecule is processed, it loses certain proteins and acquires others. For example, we have seen that acquisition of cap-binding complexes, exon junction complexes, and  poly-A-binding proteins mark the completion of capping, splicing, and poly-A addition, respectively. A properly completed mRNA molecule is also distinguished by the proteins it lacks. For example, the presence of an snRNP protein would signify incomplete or aberrant splicing. Only when the proteins present on an mRNA molecule collectively signify that processing was successfully completed is the mRNA exported from the nucleus into the cytosol, where it can be translated into protein. Improperly processed mRNAs and other RNA debris (excised intron sequences, for example) are retained in the nucleus, where they are eventually degraded by the nuclear exosome, a large protein complex whose interior is rich in 3ʹ-to-5ʹ RNA exonucleases 



.
Eukaryotic cells thus export only useful RNA molecules to the cytoplasm, while debris is disposed of in the nucleus. Of all the proteins that assemble on pre-mRNA molecules as they emerge from transcribing RNA polymerases, the most abundant are the hnRNPs (heterogeneous nuclear ribonuclear proteins). Some of these proteins (there are approximately 30 different ones in humans) unwind the hairpin helices in the RNA so that splicing and other signals on the RNA can be read more easily. Others preferentially package the RNA contained in the very long intron sequences typical in complex organisms (see Figure 6–31) and these may play an important role in distinguishing mature mRNA from the debris left over from RNA processing. Successfully processed mRNAs are guided through the nuclear pore complexes (NPCs)—aqueous channels in the nuclear membrane that directly connect the nucleoplasm and cytosol (Figure 6–37). Small molecules (less than 60,000 daltons) can diffuse freely through these channels. However, most of the macromolecules in cells, including mRNAs complexed with proteins, are far too large to pass through the channels without a special process. The cell uses energy to actively transport such macromolecules in both directions through the nuclear pore complexes. As explained in detail in Chapter 12, macromolecules are moved through nuclear pore complexes by nuclear transport receptors, which, depending on the identity of the macromolecule, escort it from the nucleus to the cytoplasm or vice versa. For mRNA export to occur, a specific nuclear transport receptor must be loaded onto the mRNA, a step that, in many organisms, takes place in concert with 3ʹ cleavage and polyadenylation. Once it helps to move an RNA molecule through the nuclear pore complex, the transport receptor dissociates from the mRNA, re-enters the nucleus, and is then used to export a new mRNA molecule. The export of mRNA–protein complexes from the nucleus can be readily observed with the electron microscope for the unusually abundant mRNA of the insect Balbiani Ring genes. As these genes are transcribed, the newly formed RNA is seen to be packaged by proteins, including hnRNPs, SR proteins, and components of the spliceosome. This protein–RNA complex undergoes a series of structural transitions, probably reflecting RNA processing events, culminating in a curved fiber.




This curved fiber moves through the nucleoplasm and enters the nuclear pore complex (with its 5ʹ cap proceeding first), and it then undergoes another series of structural transitions as it moves through the pore. These and other observations reveal that the pre-mRNA–protein and mRNA–protein complexes are dynamic structures that gain and lose numerous specific proteins during RNA synthesis, processing, and export.

Proteins Can Move Between Compartments in Different Ways
The synthesis of all proteins begins on ribosomes in the cytosol, except for the few that are synthesized on the ribosomes of mitochondria and plastids. Their subsequent fate depends on their amino acid sequence, which can contain sorting signals that direct their delivery to locations outside the cytosol or to organelle surfaces. Some proteins do not have a sorting signal and consequently remain in the cytosol as permanent residents. Many others, however, have specific sorting signals that direct their transport from the cytosol into the nucleus, the ER, mitochondria, plastids, or peroxisomes; sorting signals can also direct the transport of proteins from the ER to other destinations in the cell.

To understand the general principles by which sorting signals operate, it is important to distinguish three fundamentally different ways by which proteins move from one compartment to another. These three mechanisms are described below, and the transport steps at which they operate are outlined in the picture below:

A simplified “roadmap” of protein traffic within a eukaryotic cell. Proteins can move from one compartment to another by

gated transport (red)
protein translocation (blue)
or vesicular transport (green)


The sorting signals that direct a given protein’s movement through the system, and thereby determine its eventual location in the cell, are contained in each protein’s amino acid sequence. The journey begins with the synthesis of a protein on a ribosome in the cytosol and, for many proteins, terminates when the protein reaches its final destination. Other proteins shuttle back and forth between the nucleus and cytosol. At each intermediate station (boxes), a decision is made as to whether the protein is to be retained in that compartment or transported further. A sorting signal may direct either retention in or exit from a compartment. We shall refer to this figure often as a guide in this chapter and the next, highlighting in color the particular pathway being discussed.



The transfer of soluble proteins from the ER to the Golgi apparatus, for example, occurs in this way. Because the transported proteins do not cross a membrane, vesicular transport can move proteins only between compartments that are topologically equivalent



Each mode of protein transfer is usually guided by sorting signals in the transported protein, which are recognized by complementary sorting receptors. If a large protein is to be imported into the nucleus, for example, it must possess a sorting signal that receptor proteins recognize to guide it through the nuclear pore complex. If a protein is to be transferred directly across a membrane, it must possess a sorting signal that the translocator recognizes. Likewise, if a protein is to be loaded into a certain type of vesicle or retained in certain organelles, a complementary receptor in the appropriate membrane must recognize its sorting signal.

Signal Sequences and Sorting Receptors Direct Proteins to the Correct Cell Address
Most protein sorting signals involved in transmembrane transport reside in a stretch of amino acid sequence, typically 15–60 residues long. Such signal sequences are often found at the  N-terminus of the polypeptide chain, and in many cases specialized signal peptidases remove the signal sequence from the finished protein once the sorting process is complete. Signal sequences can also be internal stretches of amino acids, which remain part of the protein. Such signals are used in gated transport into the nucleus. Sorting signals can also be composed of multiple internal amino acid sequences that form a specific three-dimensional arrangement of atoms on the protein’s surface; such signal patches are sometimes used for nuclear import and in vesicular transport. Each signal sequence specifies a particular destination in the cell. Proteins destined for initial transfer to the ER usually have a signal sequence at their Nterminus that characteristically includes a sequence composed of about 5–10 hydrophobic amino acids. Many of these proteins will in turn pass from the ER to the Golgi apparatus, but those with a specific signal sequence of four amino acids at their C-terminus are recognized as ER residents and are returned to the ER. Proteins destined for mitochondria have signal sequences of yet another type, in which positively charged amino acids alternate with hydrophobic ones. Finally, many proteins destined for peroxisomes have a signal sequence of three characteristic amino acids at their C-terminus. The table below presents some specific signal sequences.



Question : How could these sequences have evolved ? trial and error ?


Experiments in which the peptide is transferred from one protein to another by genetic engineering techniques have demonstrated the importance of each of these signal sequences for protein targeting. Placing the N-terminal ER signal sequence at the beginning of a cytosolic protein, for example, redirects the protein to the ER; removing or mutating the signal sequence of an ER protein causes its retention in the cytosol. Signal sequences are therefore both necessary and sufficient for protein targeting. Even though their amino acid sequences can vary greatly, the signal sequences of proteins having the same destination are functionally interchangeable; physical properties, such as hydrophobicity, often seem to be more important in the signal- recognition process than the exact amino acid sequence. Signal sequences are recognized by complementary sorting receptors that guide proteins to their appropriate destination, where the receptors unload their cargo. The receptors function catalytically: after completing one round of targeting, they return to their point of origin to be reused. Most sorting receptors recognize classes of proteins rather than an individual protein species. They can therefore be viewed as public transportation systems, dedicated to delivering numerous different components to their correct location in the cell.
The Transport of Molecules Between the Nucleus and the Cytosol
The nuclear envelope encloses the DNA and defines the nuclear compartment. This envelope consists of two concentric membranes, which are penetrated by nuclear pore complexes

The nuclear envelope. The double-membrane envelope is penetrated by pores in which nuclear pore complexes (not shown) are positioned. The outer nuclear membrane is continuous with the endoplasmic reticulum (ER). The ribosomes that are normally bound to the cytosolic surface of the ER membrane and outer nuclear membrane are not shown.
The nuclear lamina is a fibrous protein meshwork underlying the inner membrane.





Although the inner and outer nuclear membranes are continuous, they maintain distinct protein compositions. The inner nuclear membrane contains proteins that act as binding sites for chromosomes and for the  nuclear lamina, a protein meshwork that provides structural support for the nuclear envelope; the lamina also acts as an anchoring site for chromosomes and the cytoplasmic cytoskeleton (via protein complexes that span the nuclear envelope). The inner membrane is surrounded by the outer nuclear membrane, which is continuous with the membrane of the ER. Like the ER membrane, the outer nuclear membrane is studded with ribosomes engaged in protein synthesis. The proteins made on these ribosomes are transported into the space between the inner and outer nuclear membranes (the perinuclear space), which is continuous with the ER lumen . Bidirectional traffic occurs continuously between the cytosol and the nucleus. The many proteins that function in the nucleus—including histones, DNA polymerases, RNA polymerases, transcriptional regulators, and RNA-processing proteins— are selectively imported into the nuclear compartment from the cytosol, where they are made. At the same time, almost all RNAs—including mRNAs, rRNAs, tRNAs, miRNAs, and snRNAs—are synthesized in the nuclear compartment and then exported to the cytosol. Like the import process, the export process is selective; mRNAs, for example, are exported only after they have been properly modified by RNA-processing reactions in the nucleus. In some cases, the transport process is complex. Ribosomal proteins, for instance, are made in the cytosol and imported into the nucleus, where they assemble with newly made ribosomal RNA into particles. The particles are then exported to the cytosol, where they assemble into ribosomes. Each of these steps requires selective transport across the nuclear envelope.

Nuclear Localization Signals Direct Nuclear Proteins to the Nucleus
When proteins are experimentally extracted from the nucleus and reintroduced into the cytosol, even the very large ones reaccumulate efficiently in the nucleus. Sorting signals called nuclear localization signals (NLSs) are responsible for the selectivity of this active nuclear import process. The signals have been precisely defined by using recombinant DNA technology for numerous nuclear proteins, as well as for proteins that enter the nucleus only transiently



In many nuclear proteins, the signals consist of one or two short sequences that are rich in the positively charged amino acids lysine and arginine, with the precise sequence varying for different proteins. Other nuclear proteins contain different signals, some of which are not yet characterized. Nuclear localization signals can be located almost anywhere in the amino acid sequence and are thought to form loops or patches on the protein surface. Many function even when linked as short peptides to lysine side chains on the surface of a cytosolic protein, suggesting that the precise location of the signal within the amino acid sequence of a nuclear protein is not important. Moreover, as long as one of the protein subunits of a multicomponent complex displays a nuclear localization signal, the entire complex will be imported into the nucleus. Macromolecular transport across NPCs differs fundamentally from the transport of proteins across the membranes of other organelles, in that it occurs through a large, expandable, aqueous pore, rather than through a protein transporter spanning one or more lipid bilayers. For this reason, fully folded nuclear proteins can be transported into the nucleus through an NPC, and newly formed ribosomal subunits are transported out of the nucleus as an assembled particle. By contrast, proteins have to be extensively unfolded to be transported into most other organelles.

Nuclear Import Receptors Bind to Both Nuclear Localization Signals and NPC Proteins
To initiate nuclear import, most nuclear localization signals must be recognized by nuclear import receptors, sometimes called importins, most of which are encoded by a family of related genes. Each family member encodes a receptor protein that can bind and transport the subset of cargo proteins containing the appropriate nuclear localization signal



Nuclear import receptors do not always bind to nuclear proteins directly. Additional adaptor proteins can form a bridge between the import receptors and the nuclear localization signals on the proteins to be transported (Figure 1B above). Some adaptor proteins are structurally related to nuclear import receptors. By using a variety of import receptors and adaptors, cells are able to recognize the broad repertoire of nuclear localization signals that are displayed on nuclear proteins. The import receptors are soluble cytosolic proteins that bind both to the nuclear localization signal on the cargo protein and to the phenylalanine-glycine (FG) repeats in the unstructured domains of the channel nucleoporins that line the central pore. FG-repeats are also found in the cytoplasmic and nuclear fibrils. FG-repeats in the unstructured tangle of the pore are thought to do doubleduty. They interact weakly, which gives the protein tangle gel-like properties that impose a permeability barrier to large macromolecules, and they serve as docking sites for nuclear import receptors. FG-repeats line the path through the NPCs taken by the import receptors and their bound cargo proteins. According to one model of nuclear transport, the receptor–cargo complexes move along the transport path by repeatedly binding, dissociating, and then re-binding to adjacent FG-repeat sequences. In this way, the complexes may hop from one nucleoporin to another to traverse the tangled interior of the NPC in a random walk. As import receptors bind to FG-repeats during this journey, they would disrupt interaction between the repeats and locally dissolve the gel phase of the protein tangle that fills the pore, allowing the passage of the receptor–cargo complex. Once inside the nucleus, the import receptors dissociate from their cargo and return to the cytosol. As we will see, this dissociation only occurs on the nuclear side of the NPC and thereby confers directionality to the import process.

Nuclear Export Works Like Nuclear Import, But in Reverse
The nuclear export of large molecules, such as new ribosomal subunits and RNA molecules, occurs through NPCs and also depends on a selective transport system. The transport system relies on nuclear export signals on the macromolecules to be exported, as well as on complementary nuclear export receptors, or exportins. These receptors bind to both the export signal and NPC proteins to guide their cargo through the NPC to the cytosol. Many nuclear export receptors are structurally related to nuclear import receptors, and they are encoded by the same gene family of nuclear transport receptors, or karyopherins. In yeast, there are 14 genes encoding karyopherins; in animal cells, the number is significantly larger. It is often not possible to tell from their amino acid sequence alone whether a particular family member works as a nuclear import or nuclear export receptor. As might be expected, therefore, the import and export transport systems work in similar ways but in opposite directions: the import receptors bind their cargo molecules in the cytosol, release them in the nucleus, and are then exported to the cytosol for reuse, while the export receptors function in the opposite fashion.

In other words: Gate chip code authentication: 4  Here’s a illustration:  A round door needs to be open to the environment, but keep interlopers out.  Valid users, coming in a wide variety of sizes, need to be allowed access by an automatic authentication system that will usher them in quickly.  Once inside, they should not be able to drift back out.  The nuclear pore complex appears to use a most elegant solution to this problem of “selective gating.”  Imagine a spaceship with a highly-sensitive computer center at its core.  Objects and spacemen drift by in this weightless environment.  The doors to the computer center must remain open at all times, but entry must be protected from enemies and from those who have no business being in there.  Anchored to the rims of these doors are chains that extend outward, drifting about like spaghetti in a breeze tied at one end.  The ends of these chains contain crystals that emit a force-field, collectively creating an invisible dome of force around the door, preventing accidental or malicious entry.You, as a valid user, approach the door with a secret crystal in your hand that acts like an authentication chip code.  When you extend it toward the chains, they sense it, and rapidly collapse backwards, pulling you in and forming a kind of tunnel around you.  The more distant chains are not affected; they continue to stand guard and keep the force field up.  Once you are inside, a robotic device removes your code chip and secures it in a protective chamber so that it cannot open the door behind you.  Meanwhile, the collapsed chains quickly extend outward again, re-establishing the force field to keep out anything or anybody not having the special chip code.

“The nuclear pore complex regulates cargo transport between the cytoplasm and the nucleus.  We set out to correlate the governing biochemical interactions to the nanoscopic responses of the phenylalanineglycine (FG) rich nucleoporin domains, which are involved in attenuating or promoting cargo translocation.  We found that binding interactions with the transport receptor karyopherin-[Beta]1 caused the FG domains of the human nucleoporin Nup153 to collapse into compact molecular conformations.  This effect was reversed by the action of Ran guanosine triphosphate, which returned the FG domains into a polymer brush-like, entropic barrier conformation.  Similar effects were observed in Xenopus oocyte nuclei in situ.  Thus, the reversible collapse of the FG domains may play an important role in regulating nucleocytoplasmic transport.”
    

Question : How could this communication system have evolved ?





Three subsets of sequence complexity and their relevance to biopolymeric information 3
In summary, Sequence complexity can be

1) random (RSC)
2) ordered (OSC)
3) functional (Functional Sequence Complexity)


FSC is the product of nonrandom selection. FSC results from the equivalent of a succession of integrated algorithmic decision node "switch settings." FSC alone instructs sophisticated metabolic function. Self-ordering processes preclude both complexity and sophisticated functions. Self-ordering phenomena are observed daily in accord with chaos theory. But under no known circumstances can self-ordering phenomena like hurricanes, sand piles, crystallization, or fractals produce algorithmic organization. Algorithmic "self-organization" has never been observed  despite numerous publications that have misused the term . Bone fide organization always arises from choice contingency, not chance contingency or necessity.

Reduced uncertainty (misnamed "mutual entropy") cannot measure prescriptive information (information that specifically informs or instructs). Any sequence that specifically informs us or prescribes how to achieve success inherently contains choice controls. The constraints of physical dynamics are not choice contingent. Prescriptive sequences are called "instructions" and "programs." They are not merely complex sequences. They are algorithmically complex sequences. They are cybernetic. Random sequences are maximally complex. But they don't do anything useful. Algorithmic instruction is invariably the key to any kind of sophisticated organization such as we observe in any cell. No method yet exists to quantify "prescriptive information" (cybernetic "instructions").

Nucleic acid prescription of function cannot be explained by "order out of chaos" or by "order on the edge of chaos" . Physical phase changes cannot write algorithms. Biopolymeric matrices of high information retention are among the most complex entities known to science. They do not and can not arise from low-informational self-ordering phenomena.
Export Proteins 5
Some proteins involved in the translocation of mRNA through the nuclear pore »

Adaptors as export signals:
Substances, like mRNA, that are transported from the nucleus to the cytoplasm, contain an export signal that serves as a label saying "I should be transported to the cytoplasm". The label is recognized by export receptors. It is probably not the mRNA itself, but rather proteins associated with the mRNA, which are recognized by the export receptors. For example, some common proteins associated with mRNA (like HnRNP A1 and HnRNP K) have been shown to contain export signals.

Also the proteins associated with the 5' end CAP of the mRNA (called Cap Binding Complex CBC) acts as export signal. They are not crucial for the transport of mRNA, but may play a role in the directional translocation since the 5' end of the mRNA is transported in the lead.

Export receptors:
Export receptors bind to the export signals and carry the cargo (the mRNA) to the other side of the nuclear pore complex. In the case of mRNA transport, an export receptor called CRM1 is believed to be important.

Directional transport:
In order for the export protein to bind to the export signal on the cargo, a protein called RanGTP is needed. The whole complex (the mRNA with the proteins acting as export signals, the export receptor and RanGTP) is transported together through the nuclear pore complex, from the nucleus to the cytoplasm. In the cytoplasm, the complex disassociates and in this process RanGTP is hydrolized to RanGDP. The receptors are then recycled to the nucleus.

mRNA may only be transported from the nucleus to the cytoplasm and not in the other direction. The assymetry of RanGTP/RanGDP is thought to be one important factor of this directional transport of mRNA.

1) http://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.0020380
2) https://en.wikipedia.org/wiki/Cell_nucleus
3) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1208958/
4) http://crev.info/2007/11/more_cell_codes_and_authentication_mechanisms/#sthash.RvV6qc76.dpuf
5) http://www.nobelprize.org/educational/medicine/dna/a/transport/export_proteins.html



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Subcellular mRNA localisation at a glance 1

mRNA localisation coupled to translational regulation provides an important means of dictating when and where proteins function in a variety of model systems. This mechanism is particularly relevant in polarised or migrating cells. Although many of the models for how this is achieved were first proposed over 20 years ago, some of the molecular details are still poorly understood. Nevertheless, advanced imaging, biochemical and computational approaches have started to shed light on the cis-acting localisation signals and trans-acting factors that dictate the final destination of localised transcripts. In this Cell Science at a Glance article and accompanying poster, we provide an overview of mRNA localisation, from transcription to degradation, focusing on the microtubule-dependent active transport and anchoring mechanism, which we will use to explain the general paradigm. However, it is clear that there are diverse ways in which mRNAs become localised and target protein expression, and we highlight some of the similarities and differences between these mechanisms.
















1) http://jcs.biologists.org/content/127/10/2127.full.pdf

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Intracellular communication

Cell signaling 3 is part of a complex system of communication that governs basic cellular activities and coordinates cell actions. The ability of cells to perceive and correctly respond to their microenvironment is the basis of development, tissue repair, and immunity as well as normal tissue homeostasis. Errors in cellular information processing are responsible for diseases such as cancer, autoimmunity, and diabetes.
Traditional work in biology has focused on studying individual parts of cell signaling pathways. Systems biology research helps us to understand the underlying structure of cell signaling networks and how changes in these networks may affect the transmission and flow of information. Such networks are complex systems in their organization and may exhibit a number of emergent properties including bistability and ultrasensitivity. Analysis of cell signaling networks requires a combination of experimental and theoretical approaches including the development and analysis of simulations and modeling. Long-range allostery is often a significant component of cell signaling events.
Cells have a number of signalling systems that are capable of responding either to external stimuli or to internal stimuli. In the case of the former, external stimuli acting on cell-surface receptors are coupled to transducers to relay information into the cell using a number of different signalling pathways (Pathways 1–17). Internal stimuli derived from the endoplasmic reticulum (ER) or from metabolism activate signalling pathways independently of external signals (Pathways 18 and 19). All of these pathways generate an internal messenger that then acts through an internal sensor to stimulate the effectors that bring about different cellular responses. As described in the text, the names of these signalling pathways usually reflect a major component(s) of the pathway. Signaling within, between, and among cells is subdivided into the following classifications: Intracrine signals are produced by the target cell that stay within the target cell. Autocrine signals are produced by the target cell, are secreted, and affect the target cell itself via receptors. Sometimes autocrine cells can target cells close by if they are the same type of cell as the emitting cell. An example of this are immune cells. Juxtacrine signals target adjacent (touching) cells. These signals are transmitted along cell membranes via protein or lipid components integral to the membrane and are capable of affecting either the emitting cell or cells immediately adjacent. Paracrine signals target cells in the vicinity of the emitting cell. Neurotransmitters represent an example. Endocrine signals target distant cells. Endocrine cells produce hormones that travel through the blood to reach all parts of the body.

Cells communicate with each other via direct contact (juxtacrine signaling) over short distances (paracrine signaling), or over large distances and/or scales (endocrine signaling)
Some cell–cell communication requires direct cell–cell contact. Some cells can form gap junctions that connect their cytoplasm to the cytoplasm of adjacent cells. In cardiac muscle, gap junctions between adjacent cells allows for action potential propagation from the cardiac pacemaker region of the heart to spread and coordinately cause contraction of the heart.

The notch signaling mechanism is an example of juxtacrine signaling (also known as contact-dependent signaling) in which two adjacent cells must make physical contact in order to communicate. This requirement for direct contact allows for very precise control of cell differentiation during embryonic development. In the worm Caenorhabditis elegans, two cells of the developing gonad each have an equal chance of terminally differentiating or becoming a uterine precursor cell that continues to divide. The choice of which cell continues to divide is controlled by competition of cell surface signals. One cell will happen to produce more of a cell surface protein that activates the Notch receptor on the adjacent cell. This activates a feedback loop or system that reduces Notch expression in the cell that will differentiate and that increases Notch on the surface of the cell that continues as a stem cell.

Many cell signals are carried by molecules that are released by one cell and move to make contact with another cell. Endocrine signals are called hormones. Hormones are produced by endocrine cells and they travel through the blood to reach all parts of the body. Specificity of signaling can be controlled if only some cells can respond to a particular hormone. Paracrine signals such as retinoic acid target only cells in the vicinity of the emitting cell.[6] Neurotransmitters represent another example of a paracrine signal. Some signaling molecules can function as both a hormone and a neurotransmitter. For example, epinephrine and norepinephrine can function as hormones when released from the adrenal gland and are transported to the heart by way of the blood stream. Norepinephrine can also be produced by neurons to function as a neurotransmitter within the brain.[7] Estrogen can be released by the ovary and function as a hormone or act locally via paracrine or autocrine signaling.[8] Active species of oxygen and nitric oxide can also act as cellular messengers. This process is dubbed redox signaling.



Understanding Cells: Think Information, Logic Circuits1


The Concepts article in Nature 08/21/2003 is about “Systems biology: Understanding Cells” by Paul Nurse.  A striking feature of his article is the repeated use of the word information:

Intracellular communication include feedback loops, switches, timers, oscillators and amplifiers.  Many of these could be similar in formal structure to those already studied in the development of machine theory, computing and electronic circuitry. Nurse identifies three types of information seen in cells:
sequence data
interaction data
functional data.


He feels that this logical, informational approach to the study of cells will be more productive than just studying the individual molecules in detail: A useful analogy of what is being proposed is the analysis of an electronic circuit.  Once the detailed operations of different types of electronic components have been identified, it is possible to gain insight into what an electronic circuit can do simply by knowing what components are present and how they are connected, even if their precise dynamic behaviour has not been determined.  The various logical and informational modules implicated in a biological phenomenon of interest have to be integrated in order to generate a better understanding of how cells work.
Paul Nurse feels that this information-theoretic approach to the cell could generate a great deal of experimental work.  “The identification and characterization of these modules will require extensive experimental investigation, followed by realistic modelling of the processes involved,”  he predicts.  “Such analyses would allow a catalogue of the module types that operate in cells to be assembled.”  But this approach will work only if there is a finite set of such modules:The success of this general approach depends on there being a limited set of biochemical activities and molecular interactions that together can solve the myriad logical and informational problems found in biological systems.  If there is only a restricted set of processes that are efficient and stable in operation and which have been exploited by evolution [sic], then there should be only a limited set of possible solutions to real biological problems.  Of course, if nature shows no such restraint [sic], then we must go back to the drawing-board if we are ever to understand its complexity.
Paul Nurse is at the Cell Cycle Laboratory, Cancer Research UK, Lincoln’s Inn Fields, London.
Two things stand out from this article:
(1) The cell only makes sense when approached in terms of information and logic, and
(2) An information-theoretic approach generates productive research.
   The intelligent design (ID) community has been stressing these points for some time, but here the same thing is being stated in Nature, the most prestigious science journal in the world.  We have no inside clue on the beliefs of Paul Nurse, his feelings about ID and the origin of life, but this could have been written by Paul Nelson, a leader in the ID movement – except for that one fly-in-the-ointment personification fallacy line about the efficient processes that have been “exploited by evolution.”  That line is so out of character with the rest of the article, one wonders whether Nurse had to insert it to get it past the censors.  It adds nothing.  It looks like an obligatory pinch of incense to Emperor Darwin.The thrust of the article is that information is the key to understanding and the key to research.  Opponents of ID falsely criticize that a design-theoretic approach brings science to a screeching halt.  “God did it, and that settles it!”  Nature has just printed this refutation, showing that the opposite is true.  Everybody knows that “feedback loops, switches, timers, oscillators and amplifiers” are the products of intelligent design.  When we see similar functions in biological systems to those we understand in electronic circuits, doesn’t it make sense to study them from a design perspective?  Wouldn’t that provide the scientists with a fruitful enterprise?  Yes – unless cells turn out to be even more complex, too information-rich for our analogies with man-made circuits.  Then, the only sensible approach would be to look for deeper design, not chance!
   ID is going to save biology from implosion.  Poor Charles Atlas Darwin just can’t hold up the world any more.  If you are a scientist worried about ID, fear not.  ID will liberate science from a suffocating 19th-century ideology that didn’t know about information and logic modules at the fundamental unit of life.  You can publish your scientific papers in a secular style without needing to say the G word.  Everything will remain the same, except for some blessed subtractions: the removal of useless, foolish references to chance and Mother Nature, the tinkerer.  Instead of having to tow the line of the Darwin Party, you can look at life in a new way, and it will make sense.  As Paul Nelson stated in Unlocking the Mystery of Life, science becomes this enormous puzzle-solving expedition, in which you can expect to find rationality and beauty right at the heart of things.  It will be the beginning of another golden age of scientific discovery.

Intracellular Railroad Has Park-and-Ride System 2

Cells are like miniaturized cities, with elaborate transportation systems ferrying their cargo to and from. Just like a city may have railroads, busses, cars and monorails, the cell has multiple kinds of transport motors: dyneins, kinesins, and myosins.  Scientists have learned that most of the roadways are like one-way monorails: actin filaments and microtubules, upon which the vehicles travel in one direction.  But what if a passenger needs to jump from one system to another? ' No problem; the cell has mastered the art of ridesharing with its own park-and-ride system.

“A park-and-ride system for melanosomes.” 

Melanosomes are organelles (somes) that carry melanin, the pigment chemical that allows some organisms, including fish and amphibians, to change their skin color to match their surroundings.  For this to work, the melanosomes need to hitch rides either to the exterior of the cell or the interior.  He pulls together several recent findings to describe how this all works:
   Together these findings suggested how melanosomes might move on actin filaments and showed that this type of motility is required for the even distribution of melanosomes within the cell.  From these main observations, it became clear that, during aggregation, a cytoplasmic dynein motor carries melanosomes on the radially arranged microtubules towards the cell center (Figure 1B), while during dispersion a kinesin transports the granules to the periphery (Figure 1C), where they engage via a myosin V molecule with short actin filaments to be distributed further (Figure 1D).  This switching of transport systems is a kind of miniature edition of modern urban traffic, where millions of workers leave the city centers in the evening on trains and board their cars at park-and-ride stations to complete their daily journey within the green peripheral belt.  (Emphasis added in all quotes.)
As if that were not amazing enough, it appears that the drivers “talk” to each other with a communication system:
   Although the work of Rodionov et al. has moved the field a large step further, there are obviously several issues that remain to be investigated.  Exciting new findings addressing the coupling of motor molecules to the melanosome surface in other experimental animals open the possibility to speculate how the motors may talk to each other on a molecular level.  At least for Xenopus there is now clear evidence that both dynein and kinesin couple to melanosomes via the dynactin complex.  Moreover, both motors compete for the same protein component; this could allow one motor to gain access to the microtubule while the other is prevented from engaging successfully.
He describes how this “tug-of-war” competition is actually a kind of way for the motors to negotiate the right-of-way.  Additional factors that attach to the vehicles or trackways may assist in making sure the rules of the road are obeyed.  “Thus,” he concludes, “further exciting results are on the way to complete the picture of how melanosomes switch from one transport system to the other.” 1Marcus Maniak,
   Maniak uses the word motor 22 times in his article, which is replete with other urban metaphors: transport system, etc.  Moreover, there is no mention of evolution, Darwin, or of any mechanism that might explain how this elaborate, coordinated, interconnected system could have originated.  Surprised?

      Every muscle move you make, every breath you take, every beat of your heart, and every one of your senses are dependent on molecular machines.

 The study of biological motors and molecular machines is the “biology of the future” that Bruce Alberts, President of the National Academy of Sciences and editor of Molecular Biology of the Cell has stated more than once.  It was also a biology the likes of which Charles Darwin and his followers could not have imagined.
reliable communication requires the sender and recipient to agree upon a predetermined understanding. This agreement constitutes a code, a set of rules that converts information from  one form to another.

1) http://creationsafaris.com/crev0803.htm
2) http://creationsafaris.com/crev1203.htm#cell180
3) https://en.wikipedia.org/wiki/Cell_signaling



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Exporting RNA from the nucleus to the cytoplasm 1

The transport of RNA molecules from the nucleus to the cytoplasm is fundamental for gene expression. The different RNA species that are produced in the nucleus are exported through the nuclear pore complexes via mobile export receptors. Small RNAs (such as tRNAs and microRNAs) follow relatively simple export routes by binding directly to export receptors. Large RNAs (such as ribosomal RNAs and mRNAs) assemble into complicated ribonucleoprotein (RNP) particles and recruit their exporters via class-specific adaptor proteins. Export of mRNAs is unique as it is extensively coupled to transcription (in yeast) and splicing (in metazoa). Understanding the mechanisms that connect RNP formation with export is a major challenge in the field.

Nuclear Export of Messenger RNA 2

Transport of messenger RNA (mRNA) from the nucleus to the cytoplasm is an essential step of eukaryotic gene expression. In the cell nucleus, a precursor mRNA
undergoes a series of processing steps, including capping at the 5' ends, splicing and cleavage/polyadenylation at the 3' ends. During this process, the mRNA associates with a
wide variety of proteins, forming a messenger ribonucleoprotein (mRNP) particle. Association with factors involved in nuclear export also occurs during transcription and
processing, and thus nuclear export is fully integrated into mRNA maturation. The coupling between mRNA maturation and nuclear export is an important mechanism for providing only fully functional and competent mRNA to the cytoplasmic translational machinery, thereby ensuring accuracy and swiftness of gene expression.

Eukaryotic cells consist of various organelles that execute different activities to sustain a range of cellular functions. The largest among them is the cell nucleus, which is surrounded by the nuclear envelope (NE) and stores genetic information in the form of chromatin. Transcription of genes, processing of various RNAs and replication and repair of DNA occur in the nucleus, whereas translation of proteins exclusively takes place on the ribosomes in the cytoplasm. Due to this physical separation, messenger RNAs (mRNAs) must be exported to the cytoplasm where they direct protein synthesis, whereas proteins participate in the nuclear activities are imported into the nucleus. In addition, some types
of RNAs reenter to the nucleus after being exported to the cytoplasm. Therefore, nucleo-cytoplasmic transport of RNAs and proteins is essential for eukaryotic gene expression.

Among the various RNA species, mRNA is the most divergent in sequence, length, and structure. In addition, as recently demonstrated by proteomic analysis, mRNAs are associated with a myriad of proteins and exist as messenger ribonucleoprotein (mRNP) particles throughout their life [5,6]. The compositional complexity and the size of mRNPs are in contrast to those of other comparably small and simple RNAs, such as transfer RNAs (tRNAs) and microRNAs (miRNAs). Moreover, in the nucleus, precursor mRNAs (pre-mRNAs) undergo extensive processing including capping at the 5' end, splicing and polyadenylation at the 3' end, before being transported to the cytoplasm. Partially due to
this unusual intricacy as transport cargoes, the nuclear export mechanism of mRNA is unique and distinct from those of the other small non-coding RNAs.

Nuclear Export of mRNA: A Brief Overview

Nuclear pore complexes (NPCs), which perforate the NE, are the main gateways through which RNAs and proteins are delivered to their proper destinations. The NPC is composed of approximately 30 distinct proteins that are collectively known as nucleoporins. A subset of nucleoporins that line the central transport channel contains phenylalanine-glycine (FG)-repeat sequences, which emanate to the inside of the channel and form a dense hydrophobic meshwork that functions as a barrier limiting the improper exchange of soluble macromolecules between the nucleus and the cytoplasm. Thus, nucleo-cytoplasmic transport of RNAs and proteins requires specific transport receptors to break this barrier.

 The importin/karyopherin- family of proteins comprise the prototypical transport receptor family that mediates nucleo-cytoplasmic movement of most proteins and small non-coding RNAs, such as tRNA, uridine-rich small nuclear RNA (UsnRNA), and miRNA . These family members interact with the FG-repeats and various transport signals that are harbored in their cognate cargoes and direct them to the correct compartment. The small nuclear GTPase Ran dictates the direction of the transport mediated by the importin/karyopherin- family of transport receptors by regulating the association and dissociation of the cargo-transport receptor complexes. Nuclear export of mRNAs is a unique process that does not directly rely on the functions of the importin/karyopherin- transport receptor family and Ran. Instead, it requires the  heterodimeric transport receptors Tap-p15 (also called Nxf1-Nxt1) in metazoans and Mex67-Mtr2 in yeast.



Figure above. A brief overview of mRNA nuclear export. During transcription, protein factors required for capping, splicing and cleavage/polyadenylation are recruited to the nascent transcript, forming an mRNP. The 5' end of the mRNA is capped early in this process via an interaction between the capping enzyme and RNA polymerase II (RNAPII). Factors involved in splicing and cleavage/polyadenylation are also co-transcriptionally loaded onto the pre-mRNA. Measurement of the transcript length by the hnRNP C tetramer, which is important for allocating the transcript to the mRNA-specific processing and export pathway, could occur early during transcription. The TREX complex and a subset of the SR proteins, which are engaged in nuclear export, are recruited to the nascent mRNA via interactions with the transcription and processing factors. The nuclear export receptor Tap-p15 (Mex67-Mtr2 in yeast) in turn gains access to the mRNA via interactions with these factors as adaptors. The nuclear export receptor heterodimer facilitates the translocation of mRNPs through its interaction with FG-repeat containing nucleoporins. During the process of the nuclear mRNA biogenesis, the structure and the composition of the mRNP change drastically, and these alterations in the physicochemical properties also help the mRNP translocate through the NPC. The mRNA export factors are then dissociated from the mRNP by factors associated with the NPC to prevent the return of the mRNP to the nucleus. The exported mRNA then directs protein translation in the cytoplasm


A thermo sensitive mutant of mex67 accumulates poly (A)+ RNA in the nucleus under the non-permissive temperature . Human Tap and its orthologues from various metazoan species are also essential for cell viability, and nuclear accumulation of poly (A)+RNA was observed upon down regulation of these genes in various organisms . Although metazoan species harbor several Tap paralog genes, they are expressed only in specific tissues. Moreover, some of these proteins seem to have evolved to play other functional roles. Thus, in general, structurally diverse mRNAs are exported by a single transport receptor.

The conserved transcription-export (TREX) complex, which consists of the THO subcomplex (composed of hHpr1, Thoc2, Thoc7, Thoc5, Thoc6 and hTex1 in mammals and Hpr1, Tho2, Mft1, Thp2 and Tex1 in yeast), Uap56 (Sub2 in yeast) and Aly/REF (Yra1 in yeast) plays an important role in selection of mRNAs by Tap-p15 and Mex67-Mtr2 . The RNA-binding components of the TREX complex, including yeast Yra1 and mammalian Aly/REF, directly interact with the export receptor heterodimers, thereby functioning as adaptors.



Figure A. Structure and function of the principal mRNA export receptor Tap-p15. (A) Tap consists of an RNA recognition motif (RRM), leucine-rich repeat (LRR), nuclear transport factor 2-like (NTF2L) and ubiquitin-associated (UBA) domains. These domains are interconnected by flexible linkers (thin lines). Both the NTF2L and UBA domains contain FG-repeat-binding sites. Our recent analysis showed that the RNA binding activity of Tap is attributable to the RRM, LRR and NTF2L domains. Adaptor proteins that bind to
various domains of Tap are shown on top of the schema; (B) The structure of the NTF2L domain of Tap (green) complexed with p15 (blue). The surface of the NTF2L domain of
Tap, which is critical for its RNA-binding activity, is shown in yellow. Note that the RNA- and the FG-repeat binding sites (an FG-repeat peptide in the complex is shown in red)
are localized to opposing surfaces. The structural coordinate (accession number; 1JN5) was taken from the PDB database and displayed using the GRASP2 software.


In addition, in yeast, the serine-arginine rich (SR) proteins Npl3, Gbp2 and Hrb1, the latter two of which are associated with the TREX complex, and the mRNA binding protein Nab2 also interact with Mex67-Mtr2 and probably function as adaptors. In mammalian cells, the SR proteins 9G8 and SRp20, as well as numerous mRNA-binding proteins, have been proposed to play a similar role (Figure A) Recruitment of adaptor proteins to mRNPs is coupled with transcription and processing, causing mRNPs to be licensed to the mRNA-specific export pathway upon the completion of nuclear processing. Thus, transcription by RNA polymerase II (RNAPII) is a key determinant allocating mRNA to the appropriate export pathway. In addition, length is another important determinant that distinguishes mRNAs from UsnRNAs, both of which are transcribed by RNAPII in metazoans. The heterogeneous nuclear ribonucleoprotein (hnRNP) C tetramer, which is an abundant nuclear mRNAbinding protein, plays a critical role in this initial decision as a “molecular ruler” . Recent studies concerning genome-wide profiles of RNAPII in yeast suggest that size matters in nuclear export of mRNAs.

It has been proposed that gene positioning to NPC-proximal site (known as “gene gating” ) is coupled to transcription initiation and nuclear export of mRNA in yeast. The yeast TREX-2 complex (Sac3-Thp1-Sem1-Sus1-Cdc31), which associates with the NPC through interaction with the SAGA (Spt-Ada-Gcn5-Acetyl transferase) transcriptional co-activator complex, plays important roles in this coupling and localizes a subset of transcriptionally active genes to NPCs. Orthologues of the TREX-2 complex (GANP-PCID2-DSS1-ENY2-centrin) were also found in higher eukaryotes. In mammals, in which transcription occurs deep inside the nucleus, the Sac3 orthologue GANP (germinal-center associated nuclear protein) binds to mature mRNPs via an interaction with Tap-p15 and chaperones them from the transcription sites to NPCs. A recent report showed that the function of the mammalian TREX-2 is required for nuclear export of a subset of mRNA.

Several lines of evidence suggest that the mRNA export receptor directly interacts with an mRNA after its initial recognition via protein-protein interactions. This step has been shown to be regulated by post-translational modifications of the adaptor proteins. Subsequently, the transport receptor facilitates translocation of the bound mRNA cargo through the NPC by directly interacting with the FG-repeat sequences of nucleoporins. Upon translocation to the cytoplasm, the transport receptor is dissociated from the export complex to prevent the mRNA cargo from returning to the nucleus. This final step is facilitated by various factors, such as Gle1 and Dbp5, that are associated with the NPC.

3. Structure and Function of the mRNA-Specific Transport Receptor Heterodimer

Tap and Mex67 share a modular domain organization that comprises an RNA recognition motif (RRM) followed by leucine-rich repeat (LRR), NTF2-like (NTF2L) and ubiquitin-associated (UBA) domains  that are interconnected by unstructured flexible linkers . The NTF2L domains of Mex67 and Tap tightly interact, respectively, with the small proteins Mtr2 and p15. Structural studies have revealed that this heterodimerization with the small partner proteins is crucial for maintaining the integrity of the NTF2L domain. The NTF2L and UBA domains each contain a single FG-repeat-binding site. Although structurally unrelated, these domains bind to FG-repeat sequences in a manner similar to that of the importin/karyopherin- family transport receptors. These two FG-repeat-binding sites are essential for Tap-mediated mRNA export. Interestingly, it has been shown that Tap derivatives containing two copies of either the NTF2L or UBA domain export mRNA less efficiently than the wild type protein, suggesting that these domains are not functionally equivalent and may have additional functional roles.



1) http://www.bzh.uni-heidelberg.de/hurt/pdf/download-research-koehler-hurt.pdf
2) file:///E:/Downloads/genes-06-00163.pdf

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Cellular UPS Gets Right Packages to Chloroplasts 1

If all your packages were sent correctly over the holidays, consider the job a plant cell has getting 3000 proteins into a chloroplast.  Mistakes are not just inconvenient.  They can be deadly, or at least bring photosynthesis to a halt.  To guarantee proper delivery of components, plant cells have a remarkable shipping system, described in Current Biology by two UK biologists, Paul Javis and Colin Robinson. 2   Part of the challenge is getting polypeptides past the double membranes of the chloroplast.  A remarkable crew of enzymes and molecular machines puts a shipping label (transit peptide) on each amino acid chain, reads it, routes it to the correct destination, and then removes it

Over 90% of the ~3000 different proteins present in mature chloroplasts are encoded on nuclear DNA and translated in the cytosol

These proteins are synthesized in precursor form – each bearing an amino-terminal targeting signal called a transit peptide – and are imported into the organelle by an active, post-translational targeting process .  This process is mediated by molecular machines in the outer and inner envelope membranes, referred to as ‘translocon at the outer envelope membrane of chloroplasts’ (Toc) and ‘translocon at the inner envelope membrane of chloroplasts’ (Tic), respectively.  Upon arrival in the stroma

the transit peptide is removed and the protein either takes on its final conformation or is sorted to one of several internal compartments in a separate targeting process.

The authors believe, like most evolutionists, that plastids (including chloroplasts) arose when a primordial cell engulfed another and took over its light-harvesting machinery, a process called endosymbiosis (see 10/01/2004, 09/09/2004, 08/06/2004 and 10/07/2003 headlines, and refutation by Don Batten).  They believe the former cell that became the chloroplast retained only a stripped down version of its genetic code, and most of the DNA instructions for building these 3000 chloroplast proteins got transferred to the nucleus.  Yet this means that a tremendous amount of machinery had to be developed to get the proteins to their destinations


1) http://crev.info/2005/01/cellular_ups_gets_right_packages_to_chloroplasts/
2) http://www.sciencedirect.com/science/article/pii/S0960982204009388
3) http://crev.info/2005/01/cellular_ups_gets_right_packages_to_chloroplasts/#sthash.yI5gvdGv.dpuf



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6 Addressing proteins on Sun Aug 16, 2015 3:14 pm

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Addressing proteins 1

Even though there may be billions of possible wrong places for some proteins to go, there are very few places, sometimes just one, in which any newly made protein will fit and function. The problem is that proteins are not made where they will be used, and each one is worthless until it has found its way to the spot where it fits. How do proteins find their way?

The answer is, ‘ … newly minted proteins contain an amino acid string that determines their eventual home.’13 This string of amino acids is usually added as a tail on the end of the long­er string of amino acids which make up the protein. It has been compared to the address on an envelope. When you put a letter in the mail box without the address, what chance does it have of getting to the right person? Each properly folded protein will fit and connect correctly in only one spot, so it must be addressed correctly. ‘Misplacing a protein is more serious than losing a letter, however. “There are diseases where proteins are mistargeted in cells.”’13

In 1999, The Nobel Prize for Medicine went to Dr Guenter Blobel of The Rockefeller University in New York, for discovering the amino acid address tags that direct each protein to its proper place in the cell.

For the first cell to function, it not only had to have a way to make proteins, it also had to have solved the complex problems of folding proteins correctly, and addressing them to the exact spots where they would fit and function. Near misses in any step can cause disease.

1) http://creation.com/did-god-create-life-ask-a-protein

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