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Myofilaments: Movers and Rulers of the Sarcomere

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ABSTRACT

Striated cardiac and skeletal muscles play very different roles in the body, but they are similar at the molecular level. In particular, contraction, regardless of the type of muscle, is a precise and complex process involving the integral protein myofilaments and their associated regulatory components. The smallest functional unit of muscle contraction is the sarcomere. Within the sarcomere can be found a sophisticated ensemble of proteins associated with the thick filaments (myosin, myosin binding protein‐C, titin, and obscurin) and thin myofilaments (actin, troponin, tropomyosin, nebulin, and nebulette). These parallel thick and thin filaments slide across one another, pulling the two ends of the sarcomere together to regulate contraction. More specifically, the regulation of both timing and force of contraction is accomplished through an intricate network of intra‐ and interfilament interactions belonging to each myofilament. This review introduces the sarcomere proteins involved in striated muscle contraction and places greater emphasis on the more recently identified and less well‐characterized myofilaments: cardiac myosin binding protein‐C, titin, nebulin, and obscurin. © 2017 American Physiological Society. Compr Physiol 7:675‐692, 2017.

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Figure 1. Figure 1. Structure of sarcomere and myofilament proteins. (A) Actin and myosin overlap at the C‐zone in the A‐band where 7 to 9 MyBP‐C stripes interact with both filaments. Myosin and MyBP‐C are arranged in a ratio of ∼ 3:1. Titin spans from Z‐disk to M‐line. (B) Titin containing N2B and PEVK regions in I‐band anchors in Z‐disk via T‐cap and α‐actinin, and it also interacts with actin. (C) C‐terminal (C8‐C10) cMyBP‐C binds to meromyosin and titin, but N‐terminal C0 to M regions associate with actin and myosin head.
Figure 2. Figure 2. Schematic diagram of MyBP‐C isoforms. All three isoforms, cardiac, slow skeletal, and fast skeletal, contain a proline/alanine (P/A)‐rich region, seven immunoglobulin‐like domains (Ig), M‐domain, and three fibronectin 3 (Fn3) domains. Top: cardiac isoform of MyBP‐C has an additional C0 Ig domain at the N‐terminus and 28 residual inserts in C5 (brown vertical line). In addition, five phosphorylation sites (red vertical line) can be observed, one in the P/A region and four in M‐domain. The linker (thick purple band) between C4 and C5 is conserved between cMyBP‐C and ssMyBP‐C. Middle: fast skeletal MyBP‐C isoform is the smallest, and no phosphorylation site has been reported. Bottom: slow skeletal isoform of MyBP‐C has four phosphorylation sites, three in the P/A region and one in the M‐region.
Figure 3. Figure 3. Domain structure in I‐band region of two adult titin isoforms. Titin is a giant myofilament protein consisting of mostly Ig tandem repeats (orange), but also unique regions specific to each isoform (). Both isoforms consist of proximal poly‐Ig repeats, a variably spliced region, followed by distal poly‐Ig repeats. Isoform differences are notably distinct within the variable region. Top: N2B notably contains an N2B unique sequence, N2B‐U. Bottom: N2BA consists of a PEVK element within its variable region.
Figure 4. Figure 4. Schematic illustration of nebulin (top, >600 kDa) and nebulette (bottom, 107 kDa) structures. Nebulin spans the entire length of thin filament and has a central core region. This central sequence consists of 8 nebulin repeats, 22 nebulin super‐repeats, and an additional 23 nebulin repeats. Nebulette, the cardiac counterpart of nebulin, is much shorter and lacks nebulin super‐repeats.
Figure 5. Figure 5. Domain patterns of obscurin A and B. Both isoforms are homologous, consisting of Ig tandem repeats, Fn3 and IQ domains. The C‐terminal domains of obscurin isoforms are more variable with, for example, additional protein kinase domains and Ig domains.


Figure 1. Structure of sarcomere and myofilament proteins. (A) Actin and myosin overlap at the C‐zone in the A‐band where 7 to 9 MyBP‐C stripes interact with both filaments. Myosin and MyBP‐C are arranged in a ratio of ∼ 3:1. Titin spans from Z‐disk to M‐line. (B) Titin containing N2B and PEVK regions in I‐band anchors in Z‐disk via T‐cap and α‐actinin, and it also interacts with actin. (C) C‐terminal (C8‐C10) cMyBP‐C binds to meromyosin and titin, but N‐terminal C0 to M regions associate with actin and myosin head.


Figure 2. Schematic diagram of MyBP‐C isoforms. All three isoforms, cardiac, slow skeletal, and fast skeletal, contain a proline/alanine (P/A)‐rich region, seven immunoglobulin‐like domains (Ig), M‐domain, and three fibronectin 3 (Fn3) domains. Top: cardiac isoform of MyBP‐C has an additional C0 Ig domain at the N‐terminus and 28 residual inserts in C5 (brown vertical line). In addition, five phosphorylation sites (red vertical line) can be observed, one in the P/A region and four in M‐domain. The linker (thick purple band) between C4 and C5 is conserved between cMyBP‐C and ssMyBP‐C. Middle: fast skeletal MyBP‐C isoform is the smallest, and no phosphorylation site has been reported. Bottom: slow skeletal isoform of MyBP‐C has four phosphorylation sites, three in the P/A region and one in the M‐region.


Figure 3. Domain structure in I‐band region of two adult titin isoforms. Titin is a giant myofilament protein consisting of mostly Ig tandem repeats (orange), but also unique regions specific to each isoform (). Both isoforms consist of proximal poly‐Ig repeats, a variably spliced region, followed by distal poly‐Ig repeats. Isoform differences are notably distinct within the variable region. Top: N2B notably contains an N2B unique sequence, N2B‐U. Bottom: N2BA consists of a PEVK element within its variable region.


Figure 4. Schematic illustration of nebulin (top, >600 kDa) and nebulette (bottom, 107 kDa) structures. Nebulin spans the entire length of thin filament and has a central core region. This central sequence consists of 8 nebulin repeats, 22 nebulin super‐repeats, and an additional 23 nebulin repeats. Nebulette, the cardiac counterpart of nebulin, is much shorter and lacks nebulin super‐repeats.


Figure 5. Domain patterns of obscurin A and B. Both isoforms are homologous, consisting of Ig tandem repeats, Fn3 and IQ domains. The C‐terminal domains of obscurin isoforms are more variable with, for example, additional protein kinase domains and Ig domains.
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Teaching Material

Lin BL, Song T, Sadayappan S. Myofilaments: movers and rulers of the sarcomere. Compr Physiol 2017, 7: 675-692. doi: 10.1002/cphy.c160026

 

Didactic Synopsis

Major Teaching Points:

  The sarcomere is the functional unit of muscle contraction at the molecular level.

 

    The sarcomere consists of two sets of myofilaments, which are made up of rope-like proteins, called myofilament-associated proteins.

o             Thick filament-associated proteins include myosin, myosin binding protein-C, titin and obscurin.

o             Thin filament-associated proteins include actin, troponin, tropomyosin, and nebulin.

 

    Some myofilaments physically move to affect muscle contraction.

o             Troponin moves tropomyosin on actin to open a myosin-binding site.

o             Myosin binds actin and pulls the entire thin filament.

o             Myosin-binding protein-C regulates myosin binding to actin.

 

     While other myofilaments are rulers that measure out the filament structure, determining, where filament proteins are located on the filament.

o             Titin is the thick filament ruler.

o             Nebulin is the thin filament ruler.

o             Obscurin offers structural support.

 

     Many myofilaments have both structural and functional roles that are still being studied

 

Didactic Figure Legends

The figures—in a freely downloadable PowerPoint format—can be found on the Images tab along with the formal legends published in the article. The following legends to the same figures are written to be useful for teaching.

 

Figure 1. Teaching points: The sarcomere is the functional unit of muscle contraction at the molecular level. The basic structure of the sarcomere consists of parallel arrays of myofilament proteins. Thick and thin filament proteins slide across one another, pulling the ends of the sarcomere closer. The thick filament is primarily made of myosin, while the thin filament consists primarily of actin. The actin filament is decorated with troponin and intertwined with tropomyosin. Contraction initiates with troponin binding calcium, resulting in tropomyosin movement. This movement allows myosin to bind to actin, forming a cross-bridge. Other proteins regulate various aspects of sarcomere structure and contraction.

 

Figure 2. Teaching points: Myosin-binding protein-C (MyBP-C) interacts with both thick and thin filaments. There are two skeletal isoforms and a cardiac isoform, with noticeable differences in the N-terminal regulatory region. MyBP-C is a thick filament regulatory protein that controls the rate of contractility.

 

Figure 3. Teaching points: The domain structure of two adult titin isoforms illustrates the enormity of this giant protein. Titin spans half the sarcomere, from Z-disk to M-line. Titin regulates thick filament protein localization and is therefore known as the “thick filament ruler.”

 

Figure 4. Teaching points: Nebulin (top panel, >600 kDa) and nebulette (bottom panel, 107 kDa) proteins are the predominant skeletal and cardiac isoforms, respectively. Nebulette lacks nebulin super-repeats, and is much shorter. These proteins are known as the “thin filament ruler,” because they contribute to the regulation of thin filament length.

 

Figure 5. Teaching points: This figure illustrates domain structure of obscurin A and B, which are titin-binding signaling proteins that regulate muscle contractility. Of the three known “giant” myofilaments, obscurin is the most recently discovered.

 


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How to Cite

Brian Leei Lin, Taejeong Song, Sakthivel Sadayappan. Myofilaments: Movers and Rulers of the Sarcomere. Compr Physiol 2017, 7: 675-692. doi: 10.1002/cphy.c160026