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Titin the largest proteins known and the titin-telethonin complex - the strongest protein bond found so far in nature

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Titin the largest proteins known and titin-telethonin complex - the strongest protein bond found so far in nature

http://reasonandscience.heavenforum.org/t2671-titin-the-largest-proteins-known-and-the-titin-telethonin-complex-the-strongest-protein-bond-found-so-far-in-nature

Tintin is the Hero of a comics series by Belgian cartoonist Hergé. In molecular Biology, it is the Hero of proteins: It is the largest known protein, a giant, using up to 33000 amino acids, responsible for passive elasticity of striated muscles. It has the remarkable ability to maintain strength while stretching. A commentary in PNAS shows how another component, telethonin, sitting like a mattress between sheets of titin, contributes to the function.  “What they found was surprising: not only was this the most robust protein or protein complex ever measured, but it also could withstand nearly half the force required to break a covalent bond.  Clearly, there are some unusual features of this complex that lead to its remarkable stability.”  Titin is considered a molecular "ruler" along which the whole muscle structure is aligned, and it acts as an elastic spring when a muscle is stretched. This complex is oriented to resist forces that reflect the macroscale function of the organism – contraction and relaxation of skeletal muscles. The titin-telethonin complex is the strongest protein bond found so far in nature. The bond can be compared to a mechanical hook that holds fast when pulled upward but otherwise uncouples easily.

Titin  also known as connectin, is a protein that, in humans, is encoded by the TTN gene.Titin is a giant protein, greater than 1 µm in length, that which is responsible for the passive elasticity of muscle. It is composed of 244 individually folded protein domains connected by unstructured peptide sequences. These domains unfold when the protein is stretched and refold when the tension is removed. Titin is important in the contraction of striated muscle tissues. It connects the Z line to the M line in the sarcomere. The protein contributes to force transmission at the Z line and resting tension in the I band region. It limits the range of motion of the sarcomere in tension, thus contributing to the passive stiffness of muscle. Variations in the sequence of titin between different types of muscle (e.g., cardiac or skeletal) have been correlated with differences in the mechanical properties of these muscles. Titin is the third most abundant protein in muscle (after myosin and actin), and an adult human contains approximately 0.5 kg of titin. With its length of ~27,000 to ~33,000 amino acids (depending on the splice isoform), titin is the largest known protein. Furthermore, the gene for titin contains the largest number of exons (363) discovered in any single gene, as well as the longest single exon (17,106 bp). The human gene encoding for titin is located on the long arm of chromosome 2 and contains 363 exons, which together code for 38,138 residues (4200 kDa). 1 

Titin is an appropriately named protein active in muscle.  Its remarkable ability to maintain strength while stretching comes from the way it folds into stacks of sheet-like material.  A commentary in PNAS by Ronald S. Rock described recent work by Bertz et al that shows how another component, telethonin, sitting like a mattress between sheets of titin, contributes to the function. “What they found was surprising: not only was this the most robust protein or protein complex ever measured, but it also could withstand nearly half the force required to break a covalent bond.  Clearly, there are some unusual features of this complex that lead to its remarkable stability.”  They also found that the strength was dependent on the direction of the force applied.  This led Rock to ask, “With these key structural features identified, can we now engineer these stabilizing interactions where none existed?” 3

Muscular Protein Bond -- Strongest Yet Found In Nature 4
August 14, 2009
Scientists have shed new light on the roots of mechanical strength in muscle tissue by probing -- through single-molecule experiments -- a super-stable protein bond, the titin-telethonin complex. The real strength of any skeletal muscle doesn't start with exercise; it comes ultimately from nanoscale biological building blocks. One key element is a bond involving titin, a giant among proteins. Titin is considered a molecular "ruler" along which the whole muscle structure is aligned, and it acts as an elastic spring when a muscle is stretched.

Titin plays a role in a wide variety of muscle functions, and these, in turn, hinge on the stability with which it is anchored in a structure called the sarcomeric Z-disk




Sarcomere shortening during skeletal muscle contraction. 
(a) In the relaxed state the sarcomere, I band, and H zone are at their expanded length. The springlike action of titin molecules, which span the I band, helps pull thin and thick filaments past one another in relaxed muscle. 
(b) During muscle contraction, the Z discs at the sarcomere boundaries are drawn closer together as they move toward the ends of thick filaments in the A band. Titin molecules are compressed during contraction.

Research published in 2006 showed this anchor to be a rare palindromic arrangement of proteins – that is, it "reads" the same way forward and backward – in which two titin molecules are connected by another muscle protein, telethonin. Simulations have pointed toward a network of tight hydrogen bonds linking titin and telethonin as a source of stability. But direct measurements that would further advance this investigation have been lacking, until today's publication of experimental results in the Proceedings of the National Academy of Sciences (PNAS). 

These first-ever measurements of mechanical stability in the titin-telethonin protein complex show it to be a highly "directed" bond, extremely strong but only along the lines of natural physiological stress. Thus even at the nanoscale, this complex is oriented to resist forces that reflect the macroscale function of the organism – contraction and relaxation of skeletal muscles.

Advanced biological and physical techniques gave the researchers a handle on this nanoscale "anchor" – basically allowing them to pull on the bond from various directions and measure its performance under stress. Single-molecule force spectroscopy was performed on a custom-built atomic force microscope. Well characterized mechanical "fingerprints" made it possible to distinguish single-molecule events from non-specific interactions as well as from multi-molecule events.

Their measurements confirm that in the direction that corresponds to muscular contraction and relaxation, the titin-telethonin complex is the strongest protein bond found so far in nature. When force was applied in different directions, the proteins of the complex slid apart. The bond can be compared to a mechanical hook that holds fast when pulled upward but otherwise uncouples easily.

The researchers anticipate that directedness of protein bonds will be an important concept in studying a variety of other molecular complexes that nature subjects to mechanical strain in living organisms. 

The titin-telethonin complex is a directed, superstable molecular bond in the muscle Z-disk 5
August 11, 2009
In skeletal muscle, the giant protein titin is anchored in the Z-disk by telethonin. Much of the structural integrity of the Z-disk hinges upon the titin-telethonin bond. In this paper we show that the complex between the muscle proteins titin and telethonin forms a highly directed molecular bond. It is designed to resist ultra-high forces if they are applied in the direction along which it is loaded under physiological conditions, while it breaks easily along other directions. Highly directed molecular bonds match in an ideal way the requirements of tissues subject to mechanical stress.

Palindromic assembly of the giant muscle protein titin in the sarcomeric Z-disk 6
18 October 2005
The Z-disk of striated and cardiac muscle sarcomeres is one of the most densely packed cellular structures in eukaryotic cells It provides the architectural framework for assembling and anchoring the largest known muscle filament systems by an extensive network of protein–protein interactions, requiring an extraordinary level of mechanical stability. Here we show, using X-ray crystallography, how the amino terminus of the longest filament component, the giant muscle protein titin, is assembled into an antiparallel (2:1) sandwich complex by the Z-disk ligand telethonin. The pseudosymmetric structure of telethonin mediates a unique palindromic arrangement of two titin filaments, a type of molecular assembly previously found only in protein– DNA complexes. We have confirmed its unique architecture in vivo by protein complementation assays, and in vitro by experiments using fluorescence resonance energy transfer. The model proposed may provide a molecular paradigm of how major sarcomeric filaments are crosslinked, anchored and aligned within complex cytoskeletal networks.
 
Titin is found in multiple forms, each form produced via a process known as alternative splicing (of mRNA).  It contains 244 domains - 132 COPIES of the fibronectin type III domain and 112 COPIES of the immunoglobulin domain.* What does this mean? It means that this gene contains copies of domains found in other genes. Copies derived via duplication. This means that this gene arose primarily via the repeated duplications of these domains, and not by having bases added one at a time to a growing stretch of DNA that might one day become the Titin gene. As should be obvious, the Titin gene was not a"goal" or even a requirement of any sort - smooth muscle cells, for example, do not use Titin yet contract just fine, and the mouse Titin gene is larger than our own. In fact, running a BLAST search on the human Titin mRNA sequence, one finds multiple variants within humans, proving that the exact 80,000 bp sequence is not invariable and thus was not needed to have been produced as-is in order to be functional.

Mechanochemical evolution of the giant muscle protein titin as inferred from resurrected proteins 2
Nature magazine, 03 July 2017
We resurrect eight-domain fragments of titin corresponding to the common ancestors to mammals, sauropsids, and tetrapods, which lived 105–356 Myr ago, and compare them with titin fragments from some of their modern descendants. The main function of titin is providing passive elasticity to the muscle through acting like a spring. In addition, recent studies support an important role of the refolding of titin during contraction. It can be hypothesized that the evolution of titin has been central to the acquisition of muscle diversity in animals. However, the role of titin in evolution, for instance, during the huge physiological outbreak after the Cambrian explosion 542 Myr4, remains unexplored.

RESULTS
Reconstructing ancestral titin molecules
We used 33 protein sequences of titin from modern vertebrate species, with most of them corresponding to the complete protein sequence composed of more than 30,000 residues. The amino acid sequences were retrieved from Uniprot and GenomeNet databases containing titin from mammals, sauropsids, amphibians and ray-finned fishes (Online Methods). Using these sequences, we generated a sequence alignment and constructed a phylogenetic chronogram using Bayesian inference as well as maximum parsimony (Fig. 1b and Supplementary Fig. 1a,b).



Figure 1 Reconstruction of ancestral titin fragments. 
(a) Scheme of one half of the sarcomere from Z disk to M line. The three main sarcomeric proteins, actin, myosin and titin, are shown. The segment encompassing domains I65–I72 from the elastic part of titin has been selected for ancestral reconstruction and testing. 
(b) Uncorrelated log-normal relaxed-clock chronogram of titin with geological time inferred with Bayesian inference. A total of 33 titin genes were used. The modern species studied are indicated by the animal outlines: zebra finch, chicken, orca, rat and human. The internal nodes (circles) were selected for resurrection and laboratory testing and represent the last common ancestors of tetrapods (LTCA, 356 ± 11 Myr), sauropsids (LSCA, 278 ± 14 Myr), mammals (LMCA, 179 ± 38 Myr) and placental mammals (LPMCA, 105 ± 17 Myr).
Posterior probabilities for branch support are shown in the nodes. Geological periods are shown in the upper bar.

It has been shown that after mass extinction occurred in the late Devonian period, the so-called Hangenberg event (359 Myr ago), the majority of taxa found in fossil records were under 40 cm4. This is consistent with a global shrinkage process that occurred during the early Carboniferous period that lasted around 40 Myr. Our predicted data for LTCA, which supposedly lived after the Hangenberg event, are within the range of the sizes reported.

Titin Z1Z2-Telethonin 23



https://www.youtube.com/watch?v=CStJm9iliW4


Hello and welcome to story time with time now let's welcome our host Ty Tracy for joining me as I share another exciting literary classic this will be an amazing tale full of tension diverse domains and ultimately being stretched to the limit ladies and gentlemen this is the tale of Titin once upon a time there was a usually large protein he longed to be called the name he had always chosen for himself Titin was everyone continued to call him by his friendís birth name protein glutamine valine leucine valine glutamine and glutamine valine lysine glutamine prolene valine prolene prolene lysine baby whoa for those you don't know Titin has a longest scientific name in English language and we are not really around for that so I'll show you all the cool things about Titin.  I said previously Titin is the largest protein known to science having over 30,000 amino acids on average.  Wow that's gonna be quite a mouthful to say all at once coated by Gene TT an on chromosome number two.

Titin is found inside the sarcomeres Australia tussles in fact Titin is the third most abundant protein in your muscles so why do you care well Titin does a lot it acts as a molecular spring in the sarcomere to counteract tension it keeps the thick filament centered during contraction Titin is a structural framework associated with other proteins in the sarcomere and finally this heavyweight participates in molecular signaling all of these are incredibly important functions but for the sake of time we will just focus on the spring aspect how's that sound ty Sene cysteine tryptophan prolene glycine valine.  okay I guess we'll just go on then so let's look at the physical aspects that make this protein such an ideal marker spring so tighten this one micrometer long spanning one half the sarcomere its end terminus is bound to the z disk at the Z line over on the left and the C terminus is at the end line halfway through the sarcomere throughout this protein there are many phosphorylation sites and even a kinase domain at the C terminus these are used in the other functions of Titin mentioned earlier but we will choose to focus on the structural aspects of the a and I bands and how they help act as a spring first is the a band this sequence is highly conserved Senta acts to attach to the highly conserved myosin thick filament it will bind to both the myosin and the C protein throughout the a band you will find long-range repeating amino acid sequences known as super repeat if you compare the structure of myosin and the a band you will see these repeats match the myosin thick filaments cool huh.


 this band is made up specifically of two main globular domains amino globulin c2 and fibronectin 3 the immunoglobulin like domains as you can see are composed of two sandwiched beta sheets each sheet has four anti parallel beta strands second the fibronectin domains are very similar they are also made up of anti parallel beta sheets but this time they have about four and three for each domain however the a band is not elastic now you're probably wondering how is this molecule a spring if it's not elastic well that's where the I band comes into play Tai would you like to explain this glutamine prolene cysteine alanine glycine and I guess nevermind anyway as I said the I band is elastic able to act as a molecular spring to counteract passive and active forces on the muscle to do this the I band is made up of two domains immunoglobulin like domains and PE the K segments first off we have our old immunoglobulin friends these domains are extended under low stretch conditions so these would be conditions somewhere to passive or low muscle tension so these domains are normally forwarded into a seven strand beta of pharoah structure 

now when they do unfold the outer domains will unfold first followed later by the more central domains as you can see in this figure snuggled in between the immunoglobulin domains are many PE VK segments these are the segments that extend under high stretch conditions also they have no recognized secondary or tertiary structures but they are known for being rich in prolene glutamine valine and lysine also known as p/e VK get it it's it's name to sum up the spring-like work of the eye band first your immunoglobulin domains will extend with a PE VK regions untouched but when more force is exerted your p VK regions one Ravel this will continue until your Titan has stretched as far as it can now this stretching process is reversible as you can imagine that is essential for resetting your muscles when you aren't experiencing tension anymore current theories for such reversibility include the formation of reversible disulfide bridges between the amino acids additionally by elongating the protein you are reducing titans entropy now such reduction requires a force however when this force is removed the proteins will tend towards it's more entropic state this makes such reversibility energetically favorable so great nice quite a bit about the amazing role taking place in your body and who says science isn't fun anyway I think it's about time to get back to the tie and see where we left off in our story glutamine valine lysine and finally prolene he didn't like his name at all exciting I know so let's move on to chapter two and hear about how Titan could act as a molecular spring when tension started to grow dude we've already gone over this it's a blast but don't worry I save you some popcorn thank you for watching story time with time tune in next week to hear ty say I quit

https://www.youtube.com/watch?v=7O_ZHyPeIIA


Organization of a skeletal muscle

Muscle cells organization is highly conserved among eukaryotics 49



Sarcomeres are the repeating contractile units seen along the entire length of each myofibril and are highly characteristic features of the sarcoplasm of skeletal and cardiac muscle fibers.

Striated muscle tissue  features repeating functional units called sarcomeres, in contrast with smooth muscle tissue which does not. is so termed because the highly regular arrangement of the myofilaments creates a repeated pattern of light and dark bands.Each repeated unit is a sarcomere, the fundamental contractile unit. The borders of the sarcomere, the so-called Z-lines, are lined up in adjacent myofibrils to contribute to the striations 43 The thin filaments are attached to the Z-lines and project toward the center of the sarcomere, while the thick filaments are centered in the sarcomere. At rest, the thick and thin filaments do not overlap completely in the area near the edge of the sarcomere; rather, only thin filaments are found in this so-called I-band.

 The A-band is the region that corresponds to the length of the thick filaments. Thousands of actin filaments are arranged in parallel to one another, interdigitated with thicker filaments made of myosin. Myosin acts as a motor molecule by means of projections (arms) that “walk” along the actin filaments. In this so-called sliding-filament model, contraction of the muscle cell results from the actin and myosin filaments sliding past one another, shortening the sarcomere and ultimately the entire cell. In other words, when muscle contracts, the length of each sarcomere is reduced; that is, the distance between Z-lines diminishes. Neither the thin filaments nor the thick filaments change in length; rather, the filaments slide past each other longitudinally, such that the degree of overlap of thin and thick filaments increases. When muscle is at rest, the myosin-binding sites on the actin molecules are blocked by the regulatory protein tropomyosin (Figure below).


Molecular control of muscle contraction. 
The thin filament consists of two strands of actin twisted into a helix. (a) When a muscle is at rest, the long, rod-like tropomyosin molecule blocks the myosin-binding sites required for formation of cross-bridges. (b) When another protein complex, troponin, binds calcium ions, conformational changes lead to uncovering of the binding sites on actin. As a result, cross-bridges with myosin form, and the muscle contracts.

This, in turn, is controlled by another set of regulatory proteins, the troponin complex, which controls the positioning of tropomyosin on the thin filament. For a muscle cell to contract, the myosin-binding sites on actin must be exposed by a displacement of the troponin and tropomyosin elements. This critical step occurs when calcium ions bind to troponin, altering its interaction with tropomyosin and uncovering the myosinbinding sites on actin. In the presence of calcium, the sliding of thin and thick filaments can occur, and muscle contraction proceeds. When calcium concentrations in the cytosol fall, the binding sites on actin are covered, and contraction stops.

A skeletal muscle consists of bundles of muscle fibers called fascicles. In turn, each fascicle consists of a bundle of elongate muscle fibers (cells). The muscle fiber represents a collection of longitudinal units, the myofibrils, which in turn are composed of myofilaments of two types: thick (myosin) filaments and thin (actin) filaments. The myofilaments are organized in a specific manner that imparts a cross-striated appearance to the myofibril and to the fiber. The functional unit of the myofibril is the sarcomere; it extends in both directions from one Z line to the next Z line.

The Sarcomere
The center and the dark-staining part of each sarcomere contains the thick (myosin) filaments, which form the A band. The peripheries and the light-staining portion of the sarcomere contain the light-staining, thin actin filaments. Actin and myosin filaments are precisely aligned and stabilized within individual myofibrils and sarcomeres by accessory proteins. The thin actin filaments are bound to the protein a-actinin, which binds them to the dense Z line (band). The thick myosin filament are anchored to the Z line by the very large protein called titin. Titin positions and centers the myosin filaments on the Z line and acts like a spring between the end of the myosin filament and the Z line.

Every 1 to 2 weeks, the molecular makeup of a sarcomere is exchanged. Since these measurements were carried out at the whole heart level, it is unclear, whether different heart regions display a different dynamics in their protein turnover and how much this is affected for example by the expression of mutant and/or aggregating proteins. 56

Given the function of muscle it is not surprising that the sarcomere occupies a central position in cellular function and signalingThe sarcomere is composed of myosin and actin filaments that provide force generation and associate with the thin filament proteins that fine-tune this function. 11

Multicompartment proteins in the sarcomere 48
Published  2006
Sarcomeres, the smallest contractile units of striated muscle, are conventionally perceived as the most regular macromolecular assemblies in biology, with precisely assigned localizations for their constituent proteins. However, recent studies have revealed complex multiple locations for several sarcomere proteins within the sarcomere and other cellular compartments such as the nucleus. Several of these proteins appear to relocalize in response to mechanical stimuli. Here, we review the emerging role of these protein networks as dynamic information switchboards that communicate between the contractile machinery and the nucleus to central pathways controlling cell survival, protein breakdown, gene expression and extracellular signaling.




Organization of accessory proteins in a sarcomere. 
Each giant titin molecule extends from the Z disc to the M line—a distance of over 1 μm. Part of each titin molecule is closely associated with a myosin thick filament (which switches polarity at the M line); the rest of the titin molecule is elastic and changes length as the sarcomere contracts and relaxes. Each nebulin molecule is exactly the length of a thin filament. The actin filaments are also coated with tropomyosin and troponin and are capped at both ends. Tropomodulin caps the minus end of the actin filaments, and CapZ anchors the plus end at the Z disc, which also contains α-actinin (not shown). 



Diagram illustrating the distribution of myofilaments and accessory proteins within a sarcomere. 
The accessory proteins are titin, a large elastic molecule that anchors the thick (myosin) filaments to the Z line;
-actinin, which bundles thin  (actin) filaments into parallel arrays and anchors them at the Z line; nebulin, an elongated inelastic protein attached to the Z lines that wraps around the  thin filaments and assists
-actinin in anchoring the thin fi lament to Z lines; tropomodulin, an actin-capping protein that maintains and regulates the  length of the thin fi laments; tropomyosin, which stabilizes thin fi laments and, in association with troponin, regulates binding of calcium ions; M line proteins  (myomesin, M-protein, obscurin), which hold thick fi laments in register at the M line; myosin-binding protein C, which contributes to normal assembly of  thick filaments and interacts with titan; and two proteins (desmin and dystrophin) that anchor sarcomeres into the plasma membrane. The interactions of these various proteins maintain the precise alignment of the thin and thick filaments in the sarcomere and the alignment of sarcomeres within the cell.



Schematic representation of the dystrophin-associated glycoprotein complex.
The N-terminal, actin-binding domain of dystrophin in purple is associated with the cortical actin. The C-terminal domain associates with β-dystroglycan and with α- and β-syntrophin and dystrobrevin. nNOS is known to interact with the syntrophins as well as with caveolin. 46


Accessory proteins maintain precise alignment of thin and thick filaments within the sarcomere
To maintain efficiency and speed of muscle contraction, both thin and thick filaments in each myofibril must be aligned precisely and kept at an optimal distance from one another. Proteins known as accessory proteins are essential in regulating the spacing, attachment, and alignment of the myofilaments. These structural protein components of skeletal muscle fibrils constitute less than 25% of the total protein of the muscle fiber. They include the following :

Titin 
a large protein, spans half of the sarcomere. Titan extends from the Z line and thin filament at its N terminus toward the thick filament and M line at its C terminus. Between the thick and thin filaments, two
spring-like portions of titan help center the thick filament in the middle between two Z lines. Due to the presence of molecular “springs,” titan prevents excessive stretching of the sarcomere by developing a passive restoring force that helps with its shortening. Within muscle cells, Titin is an essential component of structures called sarcomeres.  18
An emerging role of titin beyond its properties as a passive spring is its function as a locus of signal reception and transduction. 31

Actin
is one of the major cytoskeletal proteins in eukaryotic cells and plays essential roles in a number of cellular processes including cell migration, cytokinesis, vesicle transport, and contractile force generation 26

-Actinin 
a short, bipolar, rod-shaped,  actin-binding protein, bundles thin filaments into parallel arrays and anchors them at the Z line. 
It also cross-links titin’s N terminus embedded in the Z line. α-Actinin is an evolutionarily conserved actin filament crosslinking protein with functions in both muscle and non-muscle cells. α-actinin is essential for maintaining the link between the adhesion site and the stress fibre. This conclusion was reached based on an experiment showing that laser-mediated inactivation of α-actinin located in an adhesion site resulted in stress fibre detachment from the adhesion site 8

Desmin 
an intermediate filament, forms a lattice that surrounds the sarcomere at the level of the Z lines, attaching them to one another and to the plasma membrane via linkage protein ankyrin, thus forming
stabilizing cross-links between neighboring myofibrils. Desmin Is Essential for the Tensile Strength and Integrity of Myofibrils 9  Desmin: a major intermediate filament protein essential for the structural integrity and function of muscle. 10

M line proteins
include several myosin-binding proteins that hold thick filaments in register at the M line and attach titin molecules to the thick filament. M line proteins include myomesin, M-protein, obscurin, and muscle creatine phosphatase (MM-CK).

Myomesin a-helical linkers
“As fast and reversible molecular springs the myomesin a-helical linkers are an essential component for the structural integrity of the M band.” 12

M-line proteins
These studies confirm the essential role of M-line proteins in the organization of titin filaments in the sarcomere and that the interaction between titin and M-line proteins is crucial to the formation of the M-line structure. 13

Obscurin
Essential role of obscurin in cardiac myofibrillogenesis and hypertrophic response: evidence from small interfering RNA-mediated gene silencing 14 Obscurin (B800 kDa) is another of the giant proteins expressed in the heart and skeletal muscle. It has multiple domains and is located in the periphery of Z-discs and the M-line, where it appears to interact with elements in the cytoplasm with membrane proteins such as small ankyrin 1 of the sarcoplasmic reticulum.

Creatine
Creatine has been considered essential for muscle energetics and function. Cardiovascular scientists have long regarded creatine as an essential metabolite in the network of energy transfer 15

Myosin-binding protein C (MyBP-C) 
contributes to normal assembly and to stabilization of thick filaments. It forms several distinct transverse stripes on both sides of the M line that interact with titan molecules. Myosin binding protein-C: an essential protein in skeletal and cardiac muscle16

Nebulin
Nebulin is an actin-binding protein which is localized to the thin filament of the sarcomeres in skeletal muscle. It is a very large protein  and binds as many as 200 actin monomers. Because its length is proportional to thin filament length, it is believed that nebulin acts as a thin filament "ruler" and regulates thin filament length during sarcomere assembly. Other functions of nebulin, such as a role in cell signaling, remain uncertain. 32

Dystrophin
a large protein, is thought to link laminin, which resides in the external lamina of the muscle cell, to actin filaments. Dystrophin is essential for interacting with its associated proteins and discuss the structural implications of these approaches. 17 Dystrophin is a pencil-shaped molecule that is the lynchpin between the extracellular matrix and the cytoskeleton attached to the peripheral-most myofibril of the striated muscle fiber. It is dystrophin that plays the greatest role in strengthening and maintaining the integrity of the sarcolemma during the process of contraction.

Cardiac ankyrins
Essential components for development and maintenance of excitable membrane domains in heart. 19

α-Dystroglycan
Dystrog lycan complex is a complex of two transmembrane proteins whose extracellular domains bind to laminin of the external lamina of the muscle cells. Intracellularly dystroglycan binds to dystrophin as well as to syntrophins.is essential for the induction of Egr3, a transcription factor important in muscle spindle formation. 20

Sarcoglycans
Sarcog lycan complex is composed of several transmembrane proteins localized at the costameres of the sarcolemma. They form attachments to and reinforce the dystroglycan complex.
Identification of functional domains in sarcoglycans essential for their interaction and plasma membrane targeting 21 

Protein-C ( cMyBP-C )
while cMyBP-C is not essential for sarcomere assembly and structure, it is necessary for accelerated force generation and normal cardiac function 22

Tropomyosin
The Essential Role of Tropomyosin in Cooperative Regulation of Smooth Muscle Thin Filament Activity by Caldesmon" 24

Tropomodulin
In vitro and in vivo studies reveal that tropomodulin is an actin filament pointed end capping protein, which is required to maintain the final length of thin filaments and is essential for contractile activity in embryonic chick cardiac myocytes. 25

Protein SMYD1
The myosin-interacting protein SMYD1 is essential for sarcomere organization 27

Myosin essential light chain
Structural and functional aspects of the myosin essential light chain in cardiac muscle contraction. 28

Myosin II
Myosin II (also known as conventional myosin) is the myosin type responsible for producing muscle contraction in muscle cells29

Troponin
Cardiac troponin T is essential in sarcomere assembly and cardiac contractility. 30

Nebulin
The cardiac sarcomere contains three giant proteins (titin, nebulin, and obscurin), all of which appear to have multiple roles in the assembly, maintenance, and signaling to and from the sarcomeric proteins. 31

PDZ-LIM protein
Recent work on the PDZ-LIM protein family has revealed important activities at the cellular level, mediating signals between the nucleus and the cytoskeleton, with significant impact on organ development. 33

Leiomodin
Leiomodin is an Actin Filament Nucleator in Muscle Cells. Initiation of actin polymerization in cells requires nucleation factors. Here we describe an actin-binding protein, leiomodin, which acted as a strong filament nucleator in muscle cells. 34

Calsarcins
The calcium- and calmodulin-dependent protein phosphatase calcineurin has been implicated in the transduction of signals that control the hypertrophy of cardiac muscle and slow fiber gene expression in skeletal muscle35

Zyxin
The LIM protein, zyxin, rapidly accumulates at sites of strain-induced stress fiber damage and is essential for stress fiber repair and generation of traction force. 36

N-WASP
N-WASP was required for IGF-1-induced muscle hypertrophy. These findings present the mechanisms of IGF-1-induced actin filament formation in myofibrillogenesis required for muscle maturation and hypertrophy and a mechanism of actin nucleation. 37

PDZ/LIM proteins
ALP, CLP-36 and RIL form the ALP subfamily of PDZ-LIM proteins . ALP has been implicated in sarcomere function in muscle cells in association with alpha-actinin. 38

Myomegalin
Myomegalin  is a novel A-kinase anchoring protein involved in the phosphorylation of cardiac myosin binding protein C. Cardiac contractility is regulated by dynamic phosphorylation of sarcomeric proteins by kinases such as cAMP-activated protein kinase A (PKA). Efficient phosphorylation requires that PKA be anchored close to its targets by A-kinase anchoring proteins (AKAPs). 39

Myopodin
The sarcomeric Z-disc component myopodin is a multiadapter protein that interacts with filamin and alpha-actinin. Myopodin colocalizes with filamin and alpha-actinin during all stages of muscle development. 40

Calcineurin
Elevations in intracellular calcium levels activate calcineurin, a serine/threonine phosphatase, resulting in the expression of a set of genes involved in the maintenance, growth, and remodeling of skeletal muscle. 41

C protein
C protein sensitizes certain parts of the sarcomere to calcium. As a result, the middle of the sarcomere contracts just as much as the ends, despite having much less calcium. In other words, C protein enables the sarcomeres to contract synchronously. Calcium is like the sparkplugs in an automobile engine and C protein acts like the rings that increase the efficiency of the movement of the pistons. Defects in C-protein lead to extremely serious arrhythmias, which cause sudden death when the heart loses the ability to pump blood. 44 

Spatial and temporal gradient in free calcium across the sarcomere should lead to nonuniform and inefficient activation of contraction. We show that myosin-binding protein C (MyBP-C), through its positioning on the myosin thick filaments, corrects this nonuniformity in calcium activation by exquisitely sensitizing the contractile apparatus to calcium in a manner that precisely counterbalances the calcium gradient. Thus, the presence and correct localization of MyBP-C within the sarcomere is critically important for normal cardiac function, and any disturbance of MyBP-C localization or function will contribute to the consequent cardiac pathologies. 45

Ryanodine receptors
Whenever muscles contract, so-called ryanodine receptors come into play. Calcium ions, which are ultimately responsible for the contraction of muscle cells, are released from storage organs and flow through these ion channels. Defective ryanodine receptors can lead, for example, to cardiac arrhythmias or sudden heart failure.   47 

Cap Z
A highly regular array of actin filaments is present, the location and organization of which is essential to muscle function. To understand how this regular array of actin filaments is generated, the PI is studying the actin binding protein, Cap Z. Cap Z is a heterodimeric protein (alpha and beta subunits) that binds to and blocks polymerization at the barbed (fast-growing) end of an actin filament in vitro. It is located at the Z-line of muscle in vertebrates, where the barbed end of actin filaments terminate and are anchored. Cap Z's properties in vitro and its localization in muscle suggest that it is a key component in controlling actin polymerization and/or anchoring actin filaments. 49

Cypher/ZASP
It has been demonstrated that Cypher/ZASP plays a pivotal structural role in the structural integrity of sarcomeres, and several of its mutations are associated with myopathies including dilated cardiomyopathy. 51

Ankyrin-Repeat Protein (MARP)
CARP1 (Ankrd1), CARP2 (Ankrd2/Arrp) and CARP3 (Ankrd23/DARP) are members of the muscle ankyrin-repeat protein family (MARPs) that have been shown to play important important  roles for muscle gene expression and myofilament organization 52

NBR1 and p62 cargo receptors
NBR1 has been much less studied than p62. One important study showed that NBR1 binds directly to the giant sarcomeric protein kinase titin, and that mutations in titin that disrupt the binding to NBR1, cause hereditary muscle disease in humans. NBR1 is bound both to titin and to p62 in the M line of the sarcomere and, when the binding to titin is disrupted, NBR1 and p62 are redistributed into numerous punctuated structures most likely representing so-called p62 bodies (see below). It is not known if autophagy plays any role in this disease. 53

MuRF1
MuRF1 is the only MuRF family member closely implicated in the regulation of myofibrillar proteolysis, having been linked to both cardiac atrophy and hypertrophy. 54

Flightin
Flightin Is Essential for Thick Filament Assembly and Sarcomere Stability in Drosophila Flight Muscles 55

Telethonin
The titin Z1Z2/telethonin complex, therefore, represents a tremendous opportunity to study two biological phenomena at once: 1) a multiprotein complex essential for proper muscle function 50


Schematic cross-section of the sarcomere showing major macroscopic components.
In particular, the large protein titin is illustrated along with its various domains such as I1, I27, and A168-169. The Z-disc protein telethonin is also shown interacting with two separate titin molecules at their Z1 and Z2 domains.






Sarcomeric organization and MyBP-C. 
(A) Cardiac muscle sarcomere with interdigitating thick and thin filaments. MyBP-C localized to the C-zone, whereas the ryanodine receptors are localized in puncta (CRUs) along the Z-lines, forming the boundaries of each sarcomere. 
(B) Schematic diagram of cardiac MyBP-C’s Ig-like (oval) and fibronectin-like (rectangular) domains with four phosphorylation sites (P) in the M-domain and C0C3 fragment (dashed box) used in the 3D EM and in vitro motility experiments.


Fig. 1. The structure of nebulin and the location of its binding partners.
 The basic contractile units of muscle (sarcomeres) include actin (thin) filaments, myosin (thick) filaments, and giant molecules of nebulin and titin. The thin filaments insert in the Z-disc by their barbed ends, span the I-band, interdigitate with the thick filaments in the A-band, and extend toward the M-line with their pointed ends, where tropomodulin and leiomodin bind to regulate thin filament length (note that it is not known whether tropomodulin and leiomodin can bind to the same thin filament). Nebulin is associated with the thin filament; its N-terminal region extends near the pointed end of the thin filament, and the C-terminal region is anchored within the Z-disc. The nebulin modules 1–3 (M1–3) contain the binding site for the thin filament pointed end capping protein, tropomodulin. Modules 1 through 8 connect the acidic N-terminal domain to the central, super-repeat region. This central region encompasses M9–M162, where seven module repeats (R1–R7) form 22 super repeats (S1–S22). The super repeats are characterized by potential binding motifs SDXXYK (actin-binding motif found within each module) and WLKGIGW (tropomyosin/troponin-binding motif found once in every super repeat). S21 contains the binding site for KLHL40, which belongs to the BTB-BACK-kelch family of proteins. In nebulin's C-terminal region, modules 163 through 170 connect the super repeats to the Z-line region and contain the binding site for the intermediate filament protein desmin and the thin filament barbed end capping protein, CapZ. The C-terminal region contains unique serine-rich and SH3 domains, which bind to α-actinin, titin, myopalladin, palladin, zyxin, N-WASP, Xin and XIRP2.


(a) Structure of the contractile unit of the cardiomyocyte, the sarcomere. 
As per definition, the sarcomere is flanked by a Z-disc on either side. The Z-disc has been associated with numerous mechanosensitive structures. 
(b) Close-up of the Z-disc. Localization of the potential mechanosensors nebulette, PDZ/LIM proteins, Calsarcins and Myopodin is shown. Nebulette binds to a variety of Z-disc proteins, such as actin, α-actinin, CapZ, titin, and myopalladin. PDZ/LIM proteins have been shown to bind the Z-disc associated proteins α-actinin and telethonin and a select few possess the ability to shuttle from the cytoplasm to the nucleus, where they may regulate gene transcription. Interactions of calsarcin-1 are formed with Z-disc proteins telethonin, cypher, and most importantly calcineurin  the latter in a Ca21-dependent fashion. Downstream calcineurin targets the NFAT transcription factor family. By dephosphorylating NFATs, calsarcin unmasks nuclear localization signals, which lead to the nuclear translocation of NFATs and downstream activation of gene transcription. Myopodin binds to α-actinin at the Z-disc and forms a Z-disc signaling complex with calcineurin, Ca21/calmodulin-dependent protein kinase II (CaMKII), muscle-specific A-kinase anchoring protein, and myomegalin. Upon stress, myopodin is released from α-actinin, its Z-disc anchor, before accumulating in the nucleus.


1. https://en.wikipedia.org/wiki/Titin
2. https://www.nature.com/articles/nsmb.3426
3. http://creationsafaris.com/crev200908.htm#20090811b
4. https://www.sciencedaily.com/releases/2009/07/090720190611.htm
5. http://www.pnas.org/content/106/32/13307.full
6. http://www.nature.com.https.sci-hub.hk/articles/nature04343
7. Histology A text and Atlas, page 321
8. http://www.sdbonline.org/sites/fly/genebrief/actininalpha.htm
9. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2139820/
10. https://www.ncbi.nlm.nih.gov/pubmed/15501438
11. https://www.sciencedirect.com/science/article/pii/B9780128000403000030
12. Contractile Proteins—Advances in Research and Application: 2012
13. http://onlinelibrary.wiley.com/doi/10.1002/(SICI)1097-4644(19981001)71:1%3C82::AID-JCB9%3E3.0.CO;2-Y/abstract
14. https://www.ncbi.nlm.nih.gov/pubmed/16205939
15. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3646410/
16. https://link.springer.com/article/10.1007/s10974-010-9235-4
17. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4767260/
18. https://ghr.nlm.nih.gov/gene/TTN
19. https://academic.oup.com/cardiovascres/article/71/1/22/269389
20. https://www.ncbi.nlm.nih.gov/pubmed/20213761
21. https://www.ncbi.nlm.nih.gov/pubmed/16524571
22. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3374655/
23. http://www.ks.uiuc.edu/Gallery/Posters/BPS2006/tn/z1z2.jpg.html
24. http://www.jbc.org/content/268/17/12317.full.pdf?ref=Guzels.TV
25. https://www.sciencedirect.com/science/article/pii/1050173896000229
26. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2963174/
27. https://www.ncbi.nlm.nih.gov/pubmed/21852424
28. https://www.ncbi.nlm.nih.gov/pubmed/21885653
29. https://en.wikipedia.org/wiki/Myosin
30. https://www.ncbi.nlm.nih.gov/pubmed/11967535
31. MUSCLE Fundamental Biology and Mechanisms of Disease  Volume 1,   page 164
32. https://en.wikipedia.org/wiki/Nebulin
33. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3010972/
34. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2845909/
35. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC18970/
36. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2954498/
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39. https://bmccellbiol.biomedcentral.com/articles/10.1186/1471-2121-12-18
40. https://www.ncbi.nlm.nih.gov/pubmed/20554076
41. https://www.hindawi.com/journals/bmri/2010/721219/
43. MUSCLE Fundamental Biology and Mechanisms of Disease  Volume 1, page 18
44. https://health-innovations.org/2015/02/23/researchers-identify-protein-responsible-for-keeping-the-heart-beating-on-time/
45. http://advances.sciencemag.org.sci-hub.hk/content/1/1/e1400205
46. http://www.pnas.org/content/97/25/13464.full
47. https://www.youtube.com/watch?v=tMUc5S2Pfmc
48. https://www.semanticscholar.org/paper/From-A-to-Z-and-back-Multicompartment-proteins-in-Lange-Ehler/30a1489a4d188827516554b7c09afacd4a8a5dec
49. http://grantome.com/grant/NSF/MCB-9419106
50. http://www.ks.uiuc.edu/Research/telethonin/
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Sarcomere Formation Occurs by the Assembly of Multiple Latent Protein Complexes

The stereotyped striation of myofibrils is a conserved feature of muscle organization that is critical to its function. Although most components that constitute the basic myofibrils are well-characterized biochemically and are conserved across the animal kingdom, the mechanisms leading to the precise assembly of sarcomeres, the basic units of myofibrils, are poorly understood. To gain insights into this process, we investigated the functional relationships of sarcomeric protein complexes. Specifically, we systematically analyzed, using either RNAi in primary muscle cells or available genetic mutations, the organization of myofibrils in Drosophila muscles that lack one or more sarcomeric proteins. Our study reveals that the thin and thick filaments are mutually dependent on each other for striation. Further, the tension sensor complex comprised of zipper/Zasp/α-actinin is involved in stabilizing the sarcomere but not in its initial formation. Finally, integrins appear essential for the interdigitation of thin and thick filaments that occurs prior to striation. Thus, sarcomere formation occurs by the coordinated assembly of multiple latent protein complexes, as opposed to sequential assembly.

Muscle functionality relies on the correct assembly of myofibrils, which are composed of tandem arrays of basic functional contractile units called the sarcomeres. Many mutations in genes encoding sarcomeric proteins cause muscle diseases such as congenital myopathy and dilated cardiac hypertrophy. Understanding the process of sarcomere assembly is not only relevant to the understanding of how protein complexes interact to form complex supra-molecular structures, but also of great significance to medicine for muscle diseases. Here, by taking advantage of our newly developed primary muscle cell culture method, we reevaluate sarcomere assembly by systematically analyzing the functional relationship of sarcomeric proteins using RNA interference or genetic ablation techniques. Our analysis leads us to propose a “two-state” model whereby sarcomeric proteins exist either in the “chaotic” state with independently assembled differential functional complexes or the “highly ordered suprastructure” state made from these complexes. Because we fail to detect any previously hypothesized sarcomere assembly intermediates in our system, our data support the model that sarcomere assembly is a highly coordinated process mediated by multiple latent protein complexes and does not occur in a step-wise fashion.

Muscle functionality relies on the correct assembly of myofibrils, the cylindrical organelles attached to the cell surface membrane within muscle cells that run from one end of the cell to the other end. Myofibrils are composed of tandem arrays of basic functional contractile units called the sarcomeres. Sarcomeres are highly ordered, almost crystalline-like, structures composed of thin (actin) and thick (myosin) filaments and their associated proteins (Figure 1A).


MHC is critical for muscle striation formation.
(A) Schematic organization of a myofibril, represented here with two sarcomeres. Sarcomeres are defined as the segment between two neighboring Z-lines. Thin filaments include actin filaments and their associated proteins such as troponins (Tns) (TnC, TnI, and TnT) and tropomyosin (Tm). Actin filaments are the major components of I-bands, and are cross-linked to Z-lines via α-actinin. Thick filaments are composed of myosin and are connected from the M-line to the Z-line by titin. A number of proteins important for the stability of sarcomeres, such as zipper and Zasp, are found in the Z-line.
(B) Confocal fluorescent micrographs of control muscles of a stage 17 wild-type embryo (top panels) and myosin heavy chain (Mhc) amorphic mutant muscles from Mhc1 of same stage (bottom panels) stained by phalloidin (blue in merge), anti-α-actinin (red in merge) and anti-β-integrin (green in merge). Note tht there is no obvious striation in Mhc null mutant muscles, and that β-integrin staining does not align with that of α-actinin. (C) Confocal images of control muscles of a stage 17 wild-type embryo (top panels) and Mhc1 of same stage (bottom panels) stained by anti-muscle MHC (blue in merge), anti-α-actinin (red in merge) and anti-zipper (green in merge). Note that in wild-type muscles, zipper colocalizes with α-actinin as shown in yellow in the merged image, but not with MHC. In addition, rat-anti-MHC was able to detect truncated MHC fragments in Mhc1 mutant muscles, and its staining overlaps with actin. This staining most likely reflects the ability of the Subfragment 1 region of MHC to bind to actin filaments. Scale bars: 10 µm.

Although their components have been known for many years, how the various sarcomeric proteins assemble to form these highly ordered structures is poorly understood. Understanding the process of sarcomere assembly is not only relevant to the understanding of how protein complexes interact to form complex supra-molecular structures, but is also of great significance to medicine, as many mutations in genes encoding sarcomeric proteins cause muscle diseases such as congenital myopathy and dilated cardiac hypertrophy

Muscle Giants: Molecular Scaffolds in Sarcomerogenesis
2009
Myofibrillogenesis in striated muscles is a highly complex process that depends on the coordinated assembly and integration of a large number of contractile, cytoskeletal, and signaling proteins into regular arrays, the sarcomeres. It is also associated with the stereotypical assembly of the sarcoplasmic reticulum and the transverse tubules around each sarcomere. Three giant, muscle-specific proteins, titin (3–4 MDa), nebulin (600–800 kDa), and obscurin (~720–900 kDa), have been proposed to play important roles in the assembly and stabilization of sarcomeres. 2

N-WASP, leiomodin or the formin family member FHOD3 are expressed in striated muscle and are located in the sarcomere either at the barbed (N-WASP, FHOD3) or the pointed ends (leiomodin) of the thin filaments 3

The sarcomeric cytoskeleton: from molecules to motion 4
2016
A group of proteins, summarised as the sarcomeric cytoskeleton, is essential for the ordered assembly of actin and myosin filaments into sarcomeres, by combining architectural, mechanical and signalling functions.
This review discusses recent cell biological, biophysical and structural insight into the regulated assembly of sarcomeric cytoskeleton proteins and their roles in dissipating mechanical forces in order to maintain sarcomere integrity during passive extension and active contraction. α-Actinin crosslinks in the Z-disk show a pivot-and-rod structure that anchors both titin and actin filaments. In contrast, the myosin crosslinks formed by myomesin in the M-band are of a ball-and-spring type and may be crucial in providing stable yet elastic connections during active contractions, especially eccentric exercise.

2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3076733/
3. http://www.sciencedirect.com/science/article/pii/S0167488915003821?via%3Dihub
4. http://jeb.biologists.org/content/219/2/135

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3 Evolution of striated muscles on Thu Jan 04, 2018 5:43 pm

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Evolution of striated muscles

Independent evolution of striated muscles in cnidarians and bilaterians 1
Nature. 2012 Jul 12
Striated muscles are present in bilaterian animals (e.g. vertebrates, insects, annelids) and some non-bilaterian eumetazoans (i.e. cnidarians and ctenophores). The striking ultrastructural similarity of striated muscles between these animal groups is thought to reflect a common evolutionary origin. Here we show that a muscle protein core set, including a Myosin type II Heavy Chain motor protein characteristic of striated muscles in vertebrates (MyHC-st), was already present in unicellular organisms before the origin of multicellular animals. Furthermore, myhc-st and myhc-non-muscle (myhc-nm) orthologues are expressed differentially in two sponges, compatible with the functional diversification of myhc paralogues before the origin of true muscles and the subsequent deployment of MyHC-st in fast-contracting smooth and striated muscle. Cnidarians and ctenophores possess myhc-st orthologues but lack crucial components of bilaterian striated muscles, such as troponin complex and titin genes, suggesting the convergent evolution of striated muscles. Consistently, jellyfish orthologues of a shared set of bilaterian z-disc proteins are not associated with striated muscles, but are instead expressed elsewhere or ubiquitously. The independent evolution of eumetazoan striated muscles through the addition of novel proteins to a pre-existing, ancestral contractile apparatus may serve as a paradigm for the evolution of complex animal cell types.

We have shown that cnidarians lack all molecular hallmarks of bilaterian striated muscles except myhc-st expression, and thus striated muscles in Bilateria and Hydrozoa are very likely to have evolved convergently from cells with an ancient contractile machinery . Our work revealed that the origin of many components integral to muscle cell function (notably MyHC-st) predates that of muscle cells, while others (such as the Troponin complex, Paramyosin or Titin) were acquired progressively during muscle specialisations in different animal groups

The evolutionary origin of bilaterian smooth and striated myocytes 2
Dec 1, 2016
The evolutionary origin of smooth versus striated myocytes in bilaterians accordingly remains unsolved. Ultrastructural studies have consistently documented the presence of striated somatic myocytes in virtually every bilaterian group

1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3398149/
2. https://elifesciences.org/articles/19607

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