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Thick Filament Protein Network, Functions, and Disease Association

Li Wang, Janelle Geist, Alyssa Grogan, Li‐Yen R. Hu, Aikaterini Kontrogianni‐Konstantopoulos

10.1002/cphy.c170023

Source: Volume 8, Issue 2, April 2018

Published online: March 2018

Full Article on Wiley Online Library



ABSTRACT

Sarcomeres consist of highly ordered arrays of thick myosin and thin actin filaments along with accessory proteins. Thick filaments occupy the center of sarcomeres where they partially overlap with thin filaments. The sliding of thick filaments past thin filaments is a highly regulated process that occurs in an ATP‐dependent manner driving muscle contraction. In addition to myosin that makes up the backbone of the thick filament, four other proteins which are intimately bound to the thick filament, myosin binding protein‐C, titin, myomesin, and obscurin play important structural and regulatory roles. Consistent with this, mutations in the respective genes have been associated with idiopathic and congenital forms of skeletal and cardiac myopathies. In this review, we aim to summarize our current knowledge on the molecular structure, subcellular localization, interacting partners, function, modulation via posttranslational modifications, and disease involvement of these five major proteins that comprise the thick filament of striated muscle cells. © 2018 American Physiological Society. Compr Physiol 8:631‐709, 2018.

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Figure 1. Figure 1. Schematic representation of a half sarcomere depicting the position of the Z‐disk, I‐band, A‐band, and M‐band. Myosin thick filaments and associated proteins are shown in color including myosin heads (green), myosin rods (petrol), regulatory light chains (magenta), essential light chains (peach), MyBP‐C (purple), myomesin (orange), titin (yellow), and obscurin (light blue), while actin thin filaments and the surrounding sarcoplasmic reticulum are shown in different shades of grey; the structure of the half sarcomere was generated by e‐heart.org bearing minor modifications.
Figure 2. Figure 2. Domain organization of MyHC, ELC, and RLC. (A) The NH2‐terminus of sarcomeric MyHC contains an SH3‐like domain, followed by the motor head domain containing the converter segment, a lever arm consisting of two IQ motifs, and a coiled‐coil region. Proteolytic cleavage of MyHC yields three fragments: HMM‐S1, HMM‐S2, and LMM. The S1 segment contains the SH3‐like domain, the motor head domain and the lever arm. The S2 and LMM fragments contain the NH2‐ and COOH‐terminal portions of the coiled‐coil region, respectively. (B) Both ELC and RLC contain EF‐hand motifs. ELC isoforms may contain two EF‐hand motifs, such as MYL1, or one EF‐hand motif, such as MYL3 and MYL4; however, all RLC isoforms carry two EF‐hand motifs, with MYL2 containing longer EF‐hand motifs compared to MYL7 and MYLPF.
Figure 3. Figure 3. Binding partners of myosin heavy and light chains in striated muscles. (A) A number of interacting partners have been identified for MyHC, including actin binding to the motor head domain, MyBP‐C and MyBP‐H binding to the coiled‐coil region containing both the S2 and LMM fragments, myomesin binding to the coiled‐coil LMM region, titin binding to S1 and LMM, nonerythroid 4.1R, MuRF1 and MuRF3 binding to HMM, and AMPD binding to S2. ELC and RLC bind to the NH2‐ and COOH‐terminal IQ motifs of MyHC, respectively, via their EF‐hand motifs. Although Akt2, HspB2, and caspase‐3 interact with MyHC, the exact binding sites have not been characterized yet. (B) The binding partners of ELC and RLC are less studied; ELC interacts with actin via its nonmodular NH2‐terminus, and RLC interacts with cardiac MyBP‐C, MuRF1, and MuRF2, however the exact binding sites have yet to be determined.
Figure 4. Figure 4. Schematic representation of the generation of power stroke. (A) Actomyosin interaction is inhibited upon binding of ATP to myosin. At this stage, the myosin ATPase site is partially open and inactive. (B) During recovery stroke, the converter segment of myosin is subjected to a 65° rotation resulting in closing of the myosin ATPase site and ATP hydrolysis. (C) While the hydrolysis products, ADP and inorganic phosphate, are still bound to the myosin globular head domain, the head domain weakly associates with actin and triggers the release of inorganic phosphate. Concomitantly, conformational changes of the head domain lead to enhanced actin binding, followed by release of ADP, the generation of power stroke, and muscle contraction. (D) The globular head domain of myosin is still attached to actin postpower stroke awaiting the addition of another ATP molecule and the initiation of a new cycle.
Figure 5. Figure 5. Posttranslational modifications of human myosin heavy and light chains. Given that only acetylation and phosphorylation sites are known for the human isoforms, the figure only denotes those; Tables 4 and 5 however includes additional modifications identified in other mammalian species. (A) Acetylation (Ac) and phosphorylation (P) sites of the human myosin heavy and light chains are depicted onto the myosin domains; color coding was used to note the different isoforms. With the exception of MYH7, acetylation and phosphorylation sites are mainly concentrated in the LMM coiled‐coil region. In MYH7, however, acetylation and phosphorylation sites are present throughout the entire length of the protein. (B) Acetrylation and phosphorylation sites are concentrated in the nonmodular NH2‐terminus and the first EF‐hand motif of MYL1, but only in the nonmodular NH2‐terminus of MYL3; no posttranslational modifications have been identified for MYL4. (C) Acetylation and phosphorylation sites are scattered across the entire length of MYL2 and MYLPF; similar to MYL4, there are no known posttranslational modifications for MYL7.
Figure 6. Figure 6. Number of mutations identified to date in individual domains of the myosin heavy (A) and light chain [(B) and (C)] isoforms expressed in human striated muscles. The total count noted includes missense mutations and single amino acid duplications and deletions, since these types of mutations account for >90% of the total number of mutations identified in the myosin family.
Figure 7. Figure 7. Schematic representation of the three MyBP‐C isoforms. The black and white horizontal rectangles correspond to the Pro/Ala rich region and the M‐motif, while the yellow and dark blue vertical rectangles represent Ig and FnIII domains, respectively. Colored zigzagged lines in sMyBP‐C represent alternatively spliced insertions. fMyBP‐C and cMyBP‐C share a conserved linker region between C4 and C5, denoted in red. C0 and cardiac specific regions in cMyBP‐C are shown in light blue.
Figure 8. Figure 8. Binding partners of the three MyBP‐C isoforms. Binding regions are shown on the cMyBP‐C isoform to also include interactions mediated by C0. Binding to all partners has been determined for both cMyBP‐C and sMyBP‐C unless binding is located within a cardiac specific region (light blue) or noted only for sMyBP‐C. Much less research has focused on confirming or identifying binding partners of fMyBP‐C.
Figure 9. Figure 9. Posttranslational modifications identified in cMyBP‐C and sMyBP‐C. Phosphorylation sites in sMyBP‐C and cMyBP‐C (green) are located within their NH2‐terminal regions. Acetylation of lysine residues in cMyBP‐C (purple) is primarily located in the NH2‐terminus and Ig domain C7. S‐glutathiolation of cMyBP‐C (orange) occurs in the central region of the protein within Ig domains C3‐C5. One citrulination site (blue) and one S‐nitrosylation site (gray) are located within the COOH‐terminus of cMyBP‐C. There are no known posttranslational modifications in fMyBP‐C.
Figure 10. Figure 10. Illustration of the individual (sMyBP‐C and fMyBP‐C) or number and type (cMyBP‐C) of mutations per domain that have been identified to date in the MyBP‐C family.
Figure 11. Figure 11. Domain schematic of titin within the thick filament. The various domains are depicted as differently colored rectangles with Ig domains shown in yellow, FnIII domains in dark blue, the kinase domain in pink, and interdomain sequences in orange. The two titin super repeats are also illustrated with the first one denoted by a single and the second one by a double zigzagged line connecting the respective Ig and FNIII domains.
Figure 12. Figure 12. Binding partners of titin in the thick filament. In the A‐band, the FnIII domains of titin's super repeats bind to the myosin S1 and LMM regions. Titin also provides regularly spaced binding sites for MyBPC in the first Ig domain of each second super repeat, leading to its periodic localization in the C‐zone of the A‐band. The Ig and FnIII domains located directly COOH terminally to the second super repeat mediate binding to MuRF‐1 and ‐2. In the M‐band, the titin kinase interacts with Ca2+/calmodulin and Nbr1/p62. The rest of the M‐band portion of titin provides binding sites for DRAL/FHL2, myomesin, Bin1, myospryn, calpain‐3, obscurin, and obsl1. The exact binding site for M‐protein in the COOH‐terminus of titin has not yet been identified.
Figure 13. Figure 13. Posttranslational modifications of titin within the thick filament. The only known phosphorylation sites within this region are localized to the M‐band, and include phosphorylation of the four Ser residues (Ser35236, Ser35243, Ser35249, and Ser35255; NP_001254479.2) located in the four KSP motifis present in Is4, and of Tyr‐170 located in the P+1 loop of the titin kinase domain. Moreover, eight arginylation sites are spread throughout the A‐ and M‐band portions of titin. Four of these sites (Glu14609, Glu19156, Asp19159, and Asp27727; NP_035782.3) are found within FnIII domains of the first and second super‐repeat regions, while the fifth site (Asp32535; NP_035782.3) is located in Is3. The remaining three arginylation sites are present in Ig domains in the first and second super‐repeat regions (L7960 and V15013; NP_082280.2) and the titin kinase (C24818; NP_082280.2).
Figure 14. Figure 14. Number of mutations identified to date in individual domains of titin within the thick filament. The number of missense, nonsense, indel, or splice mutations present in each domain is depicted below the schematic.
Figure 15. Figure 15. Schematic representation of the three myomesin isoforms: myomesin, M‐protein, and myomesin‐3. The yellow and dark blue rectangles correspond to Ig and FnIII domains, respectively, the black zigzagged line represents the nonmodular NH2‐terminal domain, and the red curvy line between domains My6 and My7 illustrates the Ser/Pro‐rich insertion present in EH‐myomesin.
Figure 16. Figure 16. Interacting partners of the myomesin isoforms and their respective binding sites. All three proteins form homotypic dimers via their COOH‐terminal Ig domain My13. Moreover, a number of binding sites have been identified primarily on myomesin that mediate binding to other M‐band proteins. These include the nonmodular My1 region of myomesin and Ig domains My2‐My3 of M‐protein that bind to LMM, the FnIII domains My7‐My8 of myomesin and My6‐My8 of M‐protein that interact with M‐CK, the linker region between FnIII domains My4‐My5 of myomesin that binds to the Ig3 domain of obscurin and obsl‐1, and the FnIII My4‐My6 region of myomesin that interacts with the Ig domain M4 of titin.
Figure 17. Figure 17. Illustration of the mutations that have been identified in MYOM1 encoding myomesin and their location. There are no known myopathy‐causing mutations for MYOM2 encoding M‐protein and MYOM3 encoding myomesin‐3.
Figure 18. Figure 18. Schematic representation of giant obscurin‐A and obscurin‐B and small double kinase and single kinase. Domains are shown as colored rectangles: Ig (yellow), FnIII (dark blue), IQ (green), SH3 (red), RhoGEF (purple), PH (light blue), and kinase (pink). The nonmodular region at the extreme COOH‐terminus of obscurin A is denoted as black line.
Figure 19. Figure 19. Interacting partners of obscurins in striated muscles. The NH2‐terminus of obscurins provides binding sites for several proteins residing in the M‐band, including the extreme COOH‐terminus of titin (obscurin Ig1/titin M10), sMyBP‐C v1 (obscurin Ig2/sMyBP‐C v1 C10) and myomesin (obscurin Ig3/My4‐5). Obscurin Ig58/Ig59 domains also interact with titin ZIg9/ZIg10 domains at the level of Z/I junctions. Moreover, a number of binding partners have been identified for the obscurin signaling motifs. Accordingly, the obscurin RhoGEF motif mediates binding to GTPases RhoA and TC10 and the anchoring protein RanBP9, and the obscurin IQ domain binds calmodulin in a Ca2+‐independent manner. Notably, isoform‐specific interactions have also been characterized, including the presence of multiple ankyrin binding sites in the nonmodular COOH‐terminus of obscurin‐A, and the ability of Kinase1 and Kinase2 of obscurin‐B to interact with the cytoplasmic domain of N‐cadherin and the extracellular domain of the NKA‐β1 subunit, respectively. The binding partners of the invertebrate obscurin orthlogue UNC89 are also shown in red color, although these have not yet been confirmed in vertebrates; please note that the structural architecture of the invertebrate UNC‐89 isoforms is different from the vertebrate obscurins, however the domains per se are conserved.
Figure 20. Figure 20. Posttranslational modifications of obscurins. To date, the only known modification that obscurins undergo is phosphorylation. A number of phosphorylation sites (shown in green) have been identified via phosphoproteomic analysis that exhibit a preferential accumulation within or proximal to the signaling motifs present in the COOH‐terminus. However, these have not been confirmed via biochemical or molecular methods with the exception of a phosphorylation event involving Ser4829 that is mediated by GSK‐3β and was identified in a tachypacing‐induced heart failure model.
Figure 21. Figure 21. Illustration of the OBSCN mutations and their location that have been linked with the development of different forms of cardiomyopathy. Mutations associated with HCM are shown in red, mutations associated with DCM are shown in blue, and mutations associated with LVNC are shown in black. Three additional polymorphisms have been described as compound heterozygous, and are shown in green; fs: frameshift.


Figure 1. Schematic representation of a half sarcomere depicting the position of the Z‐disk, I‐band, A‐band, and M‐band. Myosin thick filaments and associated proteins are shown in color including myosin heads (green), myosin rods (petrol), regulatory light chains (magenta), essential light chains (peach), MyBP‐C (purple), myomesin (orange), titin (yellow), and obscurin (light blue), while actin thin filaments and the surrounding sarcoplasmic reticulum are shown in different shades of grey; the structure of the half sarcomere was generated by e‐heart.org bearing minor modifications.


Figure 2. Domain organization of MyHC, ELC, and RLC. (A) The NH2‐terminus of sarcomeric MyHC contains an SH3‐like domain, followed by the motor head domain containing the converter segment, a lever arm consisting of two IQ motifs, and a coiled‐coil region. Proteolytic cleavage of MyHC yields three fragments: HMM‐S1, HMM‐S2, and LMM. The S1 segment contains the SH3‐like domain, the motor head domain and the lever arm. The S2 and LMM fragments contain the NH2‐ and COOH‐terminal portions of the coiled‐coil region, respectively. (B) Both ELC and RLC contain EF‐hand motifs. ELC isoforms may contain two EF‐hand motifs, such as MYL1, or one EF‐hand motif, such as MYL3 and MYL4; however, all RLC isoforms carry two EF‐hand motifs, with MYL2 containing longer EF‐hand motifs compared to MYL7 and MYLPF.


Figure 3. Binding partners of myosin heavy and light chains in striated muscles. (A) A number of interacting partners have been identified for MyHC, including actin binding to the motor head domain, MyBP‐C and MyBP‐H binding to the coiled‐coil region containing both the S2 and LMM fragments, myomesin binding to the coiled‐coil LMM region, titin binding to S1 and LMM, nonerythroid 4.1R, MuRF1 and MuRF3 binding to HMM, and AMPD binding to S2. ELC and RLC bind to the NH2‐ and COOH‐terminal IQ motifs of MyHC, respectively, via their EF‐hand motifs. Although Akt2, HspB2, and caspase‐3 interact with MyHC, the exact binding sites have not been characterized yet. (B) The binding partners of ELC and RLC are less studied; ELC interacts with actin via its nonmodular NH2‐terminus, and RLC interacts with cardiac MyBP‐C, MuRF1, and MuRF2, however the exact binding sites have yet to be determined.


Figure 4. Schematic representation of the generation of power stroke. (A) Actomyosin interaction is inhibited upon binding of ATP to myosin. At this stage, the myosin ATPase site is partially open and inactive. (B) During recovery stroke, the converter segment of myosin is subjected to a 65° rotation resulting in closing of the myosin ATPase site and ATP hydrolysis. (C) While the hydrolysis products, ADP and inorganic phosphate, are still bound to the myosin globular head domain, the head domain weakly associates with actin and triggers the release of inorganic phosphate. Concomitantly, conformational changes of the head domain lead to enhanced actin binding, followed by release of ADP, the generation of power stroke, and muscle contraction. (D) The globular head domain of myosin is still attached to actin postpower stroke awaiting the addition of another ATP molecule and the initiation of a new cycle.


Figure 5. Posttranslational modifications of human myosin heavy and light chains. Given that only acetylation and phosphorylation sites are known for the human isoforms, the figure only denotes those; Tables 4 and 5 however includes additional modifications identified in other mammalian species. (A) Acetylation (Ac) and phosphorylation (P) sites of the human myosin heavy and light chains are depicted onto the myosin domains; color coding was used to note the different isoforms. With the exception of MYH7, acetylation and phosphorylation sites are mainly concentrated in the LMM coiled‐coil region. In MYH7, however, acetylation and phosphorylation sites are present throughout the entire length of the protein. (B) Acetrylation and phosphorylation sites are concentrated in the nonmodular NH2‐terminus and the first EF‐hand motif of MYL1, but only in the nonmodular NH2‐terminus of MYL3; no posttranslational modifications have been identified for MYL4. (C) Acetylation and phosphorylation sites are scattered across the entire length of MYL2 and MYLPF; similar to MYL4, there are no known posttranslational modifications for MYL7.


Figure 6. Number of mutations identified to date in individual domains of the myosin heavy (A) and light chain [(B) and (C)] isoforms expressed in human striated muscles. The total count noted includes missense mutations and single amino acid duplications and deletions, since these types of mutations account for >90% of the total number of mutations identified in the myosin family.


Figure 7. Schematic representation of the three MyBP‐C isoforms. The black and white horizontal rectangles correspond to the Pro/Ala rich region and the M‐motif, while the yellow and dark blue vertical rectangles represent Ig and FnIII domains, respectively. Colored zigzagged lines in sMyBP‐C represent alternatively spliced insertions. fMyBP‐C and cMyBP‐C share a conserved linker region between C4 and C5, denoted in red. C0 and cardiac specific regions in cMyBP‐C are shown in light blue.


Figure 8. Binding partners of the three MyBP‐C isoforms. Binding regions are shown on the cMyBP‐C isoform to also include interactions mediated by C0. Binding to all partners has been determined for both cMyBP‐C and sMyBP‐C unless binding is located within a cardiac specific region (light blue) or noted only for sMyBP‐C. Much less research has focused on confirming or identifying binding partners of fMyBP‐C.


Figure 9. Posttranslational modifications identified in cMyBP‐C and sMyBP‐C. Phosphorylation sites in sMyBP‐C and cMyBP‐C (green) are located within their NH2‐terminal regions. Acetylation of lysine residues in cMyBP‐C (purple) is primarily located in the NH2‐terminus and Ig domain C7. S‐glutathiolation of cMyBP‐C (orange) occurs in the central region of the protein within Ig domains C3‐C5. One citrulination site (blue) and one S‐nitrosylation site (gray) are located within the COOH‐terminus of cMyBP‐C. There are no known posttranslational modifications in fMyBP‐C.


Figure 10. Illustration of the individual (sMyBP‐C and fMyBP‐C) or number and type (cMyBP‐C) of mutations per domain that have been identified to date in the MyBP‐C family.


Figure 11. Domain schematic of titin within the thick filament. The various domains are depicted as differently colored rectangles with Ig domains shown in yellow, FnIII domains in dark blue, the kinase domain in pink, and interdomain sequences in orange. The two titin super repeats are also illustrated with the first one denoted by a single and the second one by a double zigzagged line connecting the respective Ig and FNIII domains.


Figure 12. Binding partners of titin in the thick filament. In the A‐band, the FnIII domains of titin's super repeats bind to the myosin S1 and LMM regions. Titin also provides regularly spaced binding sites for MyBPC in the first Ig domain of each second super repeat, leading to its periodic localization in the C‐zone of the A‐band. The Ig and FnIII domains located directly COOH terminally to the second super repeat mediate binding to MuRF‐1 and ‐2. In the M‐band, the titin kinase interacts with Ca2+/calmodulin and Nbr1/p62. The rest of the M‐band portion of titin provides binding sites for DRAL/FHL2, myomesin, Bin1, myospryn, calpain‐3, obscurin, and obsl1. The exact binding site for M‐protein in the COOH‐terminus of titin has not yet been identified.


Figure 13. Posttranslational modifications of titin within the thick filament. The only known phosphorylation sites within this region are localized to the M‐band, and include phosphorylation of the four Ser residues (Ser35236, Ser35243, Ser35249, and Ser35255; NP_001254479.2) located in the four KSP motifis present in Is4, and of Tyr‐170 located in the P+1 loop of the titin kinase domain. Moreover, eight arginylation sites are spread throughout the A‐ and M‐band portions of titin. Four of these sites (Glu14609, Glu19156, Asp19159, and Asp27727; NP_035782.3) are found within FnIII domains of the first and second super‐repeat regions, while the fifth site (Asp32535; NP_035782.3) is located in Is3. The remaining three arginylation sites are present in Ig domains in the first and second super‐repeat regions (L7960 and V15013; NP_082280.2) and the titin kinase (C24818; NP_082280.2).


Figure 14. Number of mutations identified to date in individual domains of titin within the thick filament. The number of missense, nonsense, indel, or splice mutations present in each domain is depicted below the schematic.


Figure 15. Schematic representation of the three myomesin isoforms: myomesin, M‐protein, and myomesin‐3. The yellow and dark blue rectangles correspond to Ig and FnIII domains, respectively, the black zigzagged line represents the nonmodular NH2‐terminal domain, and the red curvy line between domains My6 and My7 illustrates the Ser/Pro‐rich insertion present in EH‐myomesin.


Figure 16. Interacting partners of the myomesin isoforms and their respective binding sites. All three proteins form homotypic dimers via their COOH‐terminal Ig domain My13. Moreover, a number of binding sites have been identified primarily on myomesin that mediate binding to other M‐band proteins. These include the nonmodular My1 region of myomesin and Ig domains My2‐My3 of M‐protein that bind to LMM, the FnIII domains My7‐My8 of myomesin and My6‐My8 of M‐protein that interact with M‐CK, the linker region between FnIII domains My4‐My5 of myomesin that binds to the Ig3 domain of obscurin and obsl‐1, and the FnIII My4‐My6 region of myomesin that interacts with the Ig domain M4 of titin.


Figure 17. Illustration of the mutations that have been identified in MYOM1 encoding myomesin and their location. There are no known myopathy‐causing mutations for MYOM2 encoding M‐protein and MYOM3 encoding myomesin‐3.


Figure 18. Schematic representation of giant obscurin‐A and obscurin‐B and small double kinase and single kinase. Domains are shown as colored rectangles: Ig (yellow), FnIII (dark blue), IQ (green), SH3 (red), RhoGEF (purple), PH (light blue), and kinase (pink). The nonmodular region at the extreme COOH‐terminus of obscurin A is denoted as black line.


Figure 19. Interacting partners of obscurins in striated muscles. The NH2‐terminus of obscurins provides binding sites for several proteins residing in the M‐band, including the extreme COOH‐terminus of titin (obscurin Ig1/titin M10), sMyBP‐C v1 (obscurin Ig2/sMyBP‐C v1 C10) and myomesin (obscurin Ig3/My4‐5). Obscurin Ig58/Ig59 domains also interact with titin ZIg9/ZIg10 domains at the level of Z/I junctions. Moreover, a number of binding partners have been identified for the obscurin signaling motifs. Accordingly, the obscurin RhoGEF motif mediates binding to GTPases RhoA and TC10 and the anchoring protein RanBP9, and the obscurin IQ domain binds calmodulin in a Ca2+‐independent manner. Notably, isoform‐specific interactions have also been characterized, including the presence of multiple ankyrin binding sites in the nonmodular COOH‐terminus of obscurin‐A, and the ability of Kinase1 and Kinase2 of obscurin‐B to interact with the cytoplasmic domain of N‐cadherin and the extracellular domain of the NKA‐β1 subunit, respectively. The binding partners of the invertebrate obscurin orthlogue UNC89 are also shown in red color, although these have not yet been confirmed in vertebrates; please note that the structural architecture of the invertebrate UNC‐89 isoforms is different from the vertebrate obscurins, however the domains per se are conserved.


Figure 20. Posttranslational modifications of obscurins. To date, the only known modification that obscurins undergo is phosphorylation. A number of phosphorylation sites (shown in green) have been identified via phosphoproteomic analysis that exhibit a preferential accumulation within or proximal to the signaling motifs present in the COOH‐terminus. However, these have not been confirmed via biochemical or molecular methods with the exception of a phosphorylation event involving Ser4829 that is mediated by GSK‐3β and was identified in a tachypacing‐induced heart failure model.


Figure 21. Illustration of the OBSCN mutations and their location that have been linked with the development of different forms of cardiomyopathy. Mutations associated with HCM are shown in red, mutations associated with DCM are shown in blue, and mutations associated with LVNC are shown in black. Three additional polymorphisms have been described as compound heterozygous, and are shown in green; fs: frameshift.
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Teaching Material

L. Wang, J. Geist, A. Grogan, L.-Y. R. Hu, A. Kontrogianni-Konstantopoulos. Thick Filament Protein Network, Functions, and Disease Association. Compr Physiol. 8: 2018, 631-709.

Didactic Synopsis

Major Teaching Points:

  1. Sarcomeres consist of ordered arrays of thick myosin and thin actin filaments along with accessory proteins.
  2. Myosin, the backbone of thick filaments, slides past actin filaments by hydrolyzing ATP to mediate muscle contraction.
  3. Four other proteins that are bound to thick filaments play structural and regulatory roles.
  4. Myosin binding protein-C binds to myosin and actin filaments contributing to their stabilization and modulating cross-bridge cycling.
  5. Titin binds to myosin and functions as a scaffold, signaling mediator, and mechanosensor.
  6. Myomesin forms antiparallel homodimers, cross-linking myosin, and contributing to the elasticity of thick filaments.
  7. Obscurin wraps around myofilaments over M-bands, contributing to the maintenance and alignment of thick filaments with internal membranes.
  8. The functions of myosin and its accessory proteins are regulated via alternative splicing and posttranslational modifications.
  9. Mutations in the respective genes are causatively linked to the development of skeletal and cardiac myopathies.

Didactic 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 smallest contractile unit of the striated muscle cell. One of the most remarkable features of sarcomeres is their austere periodicity created by overlapping arrays of thick myosin (A-band) and thin actin (I-band) filaments. The myosin complex composed of myosin heads and rods alongside regulatory and essential light chains is the backbone of the thick filament. In a single thick filament, the globular motor head domains of myosin face outward while their long rod regions face inward forming a bipolar filament. In addition to myosin, a number of other proteins including MyBP-C, titin, myomesin, and obscurin reside in the thick filament playing important structural and regulatory roles. In the middle of the A- and I-band, there is a vertical line called M-band and Z-disk, respectively.

Figure 2. Teaching points: Sarcomeric myosin is a hexameric motor protein composed of two MyHC, two ELC, and two RLC. Each MyHC contains a globular motor “head” domain that bears ATPase activity, a converter segment connecting the head domain to the lever arm and a “tail” that consists of a coiled-coil α-helical region that homodimerizes to form rods. Upon limited trypsin digestion, MyHC is fragmented into HMM, which contains the head region, the converter segment, the lever arm and the NH2-terminal portion of the α-helical rod domain, and light meromyosin (LMM), which contains the COOH-terminal half of the α-helical rod domain. Further cleavage of HMM by papain leads to generation of S1 and S2, with S1 consisting of the head domain, the converter segment, and the lever arm, and S2 containing the NH2-terminus of the α-helical rod domain.

Figure 3. Teaching points: Myosins form stable or transient interactions with proteins involved in different cell processes. In particular, MyHCs bind to proteins playing key roles in contractility (actin, MyBP-C and MyBP-H), cytoskeletal organization (myomesin, M-protein, titin, and nonerythroid 4.1R), signaling (PKB/Akt2), metabolism (AMPD1), protein folding and stability (HspB2 and Unc45b), proteasomal degradation (MuRFs), and apoptosis (caspase-3). Contrary to MyHC, less is known about the binding partners of ELC and RLC with the exception of their ability to interact with actin and MuRFs, respectively.

Figure 4. Teaching points: Both thin and thick filaments undergo structural alterations to accommodate actomyosin binding and the generation of power stroke. Following the generation of power stroke, the myosin head domain remains attached to actin until a new ATP molecule binds to HMM and induces detachment of the myosin head domain from actin. ATP binding to HMM further exerts a conformational strain to myosin leading to rotation of the converter domain by 65o resulting in ATP hydrolysis that enables a weak initial association of actin and myosin. As HMM alters conformation due to ATP hydrolysis, enhanced actomyosin binding occurs mediated by both stereospecific and electrostatic interactions. Following the release of ADP, the lever arm undergoes a conformational change resulting to generation of power stroke and muscle contraction.

Figure 5. Teaching points: The myosin hexamer undergoes extensive posttranslational modifications in mammals including acetylation, arginylation, phosphorylation, and O-GlcNAcylation that regulate its binding, enzymatic, and contractile properties. Notably, only acetylation and phosphorylation sites have been identified for the human isoforms. These are mainly concentrated in the LMM coiled-coil region of MyHCs, with the exception of MYH7 in which they are present throughout the entire length of the protein. Moreover, acetylation and phosphorylation sites are present in the nonmodular NH2-terminus and the first EF-hand motif of ELCs, while they are scattered across the entire length of RLCs.

Figure 6. Teaching points: Myosins are the most heavily mutated proteins in congenital and somatic cardiac and skeletal myopathies. Hundreds of mutations have been identified along the entire length of MYH7, while mutations described in MYH6 and MYH2 are preferentially localized in the motor domain and the coiled-coil region. On the contrary, MYH3 is primarily mutated within the motor domain and the lever arm. No mutations associated with myopathy have been identified in MYH1, MYH4, and MYH7B to date. In addition to mutations in MyHC, mutations in ELC and RLC also lead to disease development. MYL3 is heavily mutated in both the nonmodular NH2-terminus and the EF-hand, whereas only one mutation has been identified in MYL4 and none in MYL1. Similarly, MYL2 is heavily mutated throughout its entire length, whereas no myopathic mutations have been described in MYL7 and MYLPF.

Figure 7. Teaching points: The MyBP-C family comprises three isoforms including cMyBP-C, sMyBP-C, and fMyBP-C that play key roles in sarcomeric maintenance and cross-bridge cycling. The three isoforms share similar structures consisting of seven (sMyBP-C and fMyBP-C) or eight (cMyBP-C) Ig and three FnIII domains numbered from the NH2-terminus to the COOH-terminus as C1-C10. The cardiac isoform includes an additional Ig domain at its extreme NH2-terminus, referred to as C0. A Pro/Ala rich region and the M-motif flank C1 in all three isoforms. cMyBP-C and fMyBP-C also share a conserved linker region between Ig domains C4 and C5, which is absent from sMyBP-C. In contrast to cMyBP-C and fMyBP-C, sMyBP-C undergoes extensive alternative splicing within the Pro/Ala rich motif, the M-motif, Ig domain C7, and the extreme COOH-terminus, resulting in several sMyBP-C variants that likely play distinct structural and regulatory role in skeletal muscles.

Figure 8. Teaching points: The main binding partners of MyBP-C are actin, myosin, and titin. MyBP-C binds actin and myosin-S1 via its NH2-terminus, and these interactions are highly dynamic and regulated by Ca2+ and phosphorylation. Moreover, MyBP-C binds myosin-LMM and titin via its COOH-terminus, and these interactions are stable. In addition to the three major binding partners discussed above, isoform-specific binding partners have also been identified including obscurin and M-CK that specifically interact with sMyBP-C.

Figure 9. Teaching points: Both cMyBP-C and sMyBP-C are subjected to extensive phosphorylation within their NH2-termini that regulates their ability to modulate the formation of actomyosin cross-bridges. Interestingly, cMyBP-C is heavily phosphorylated in the M-motif, whereas sMyBP-C is primarily phosphorylated in the Pro/Ala rich region and to a lesser extent in the M-motif. In addition to phosphorylation, cMyBP-C undergoes acetylation, citrullination, S-glutathiolation, and S-nitrosylation. Acetylation primarily occurs in the NH2-terminus and Ig domain C7 likely promoting proteolysis of cMyBP-C, while S-glutathiolation takes place in the central region within Ig domains C3-C5 possibly decreasing myofilament Ca2+ sensitivity. The effect of citrullination and S-nitrosylation on the activities and stability of cMyBP-C are still unknown.

Figure 10. Teaching points: More than 500 mutations, including missense, nonsense, splice, frameshift, insertion, deletion, and indel have been described for cMyBP-C (MYBPC3 gene) that are primarily associated with the development of HCM and to a lesser extent with DCM and LVNC. These mutations are widely distributed throughout the entire length of the protein. In addition, missense and nonsense mutations in sMyBP-C (MYBPC1 gene) localizing to the NH2-terminal C1-M-C2 region of the protein have been linked to DA, AMC, and LCCS-4. Lastly, two missense mutations located in the M-motif of fMyBP-C (MYBPC2 gene) may contribute to an unclassified form of DA.

Figure 11. Teaching points: Titin, the largest known protein with a total mass of 3 to 4 MDa, spans an entire half sarcomere. The region of titin that associates with the thick filament represents 2 MDa (A-band) and 200 kDa (M-band) of titin's total mass. The region of titin that spans the A-band is composed entirely of Ig and FnIII domains (A1-170) that are organized into two types of super-repeats. The first super-repeat occurs six times in tandem and is followed by 11 copies of the second super-repeat. Titin's most COOH-terminal segment is anchored to the M-band. The M-band region is composed of an MLCK-like Ser/Thr kinase and 10 Ig domains (M1-10) that are interspersed by unique sequences, referred to as interdomain sequences 1-7 (Is1-7). Unlike the NH2-terminus and middle segment, the structure of titin within the A- and M-band is relatively rigid, inelastic, and constitutively expressed among isoforms with the exception of M-band exon 5.

Figure 12. Teaching points: A number of interacting partners have been identified within the A- and M-band portions of titin. In particular, titin contains binding sites for the sarcomeric proteins myosin, MyBP-C, myomesin, M-protein, obscurin, obsl1 and DRAL/FHL2, the E3 ligases MuRF-1 and -2, the tumor suppressor Bin1, the Ca2+-dependent cysteine preotease calpain-3, and the Ca2+-binding protein calmodulin. Moreover, the adaptor zinc-finger proteins Nbr1 and p62, which are involved in proteasomal degradation and autophagy, respectively, are substrates of TK.

Figure 13. Teaching points: The thick filament portion of titin undergoes phosphorylation within the M-band in the KSP motifs present in Is4 and the P+1 loop of TK, and arginylation throughout the A- and M-band. Although the effects of these modifications are currently elusive, it has been postulated that KSP phosphorylation is developmentally regulated and possibly plays a role in myofibrillogenesis and myocyte differentiation, while arginylation may regulate passive force likely by modifying titin's anchorage to the thick filament.

Figure 14. Teaching points: To date, a total of 175 mutations have been identified in the region of titin spanning the A- and M-band. The majority of these mutations (132) are linked to a variety of cardiomyopathies, including DCM, HCM, and ARVC. The remaining mutations are linked to skeletal muscle disorders including TMD, LGMD2J, EDMD, HMERF, CNM, and multiminicore disease with associated heart disease.

Figure 15. Teaching points: The myomesin family comprises a group of three modular proteins, myomesin, M-protein, and myomesin-3 that reside in the sarcomeric M-band where they cross-link myosin filaments and maintain their proper alignment. The three isoforms have similar architectures, and are composed of 13 domains that include a nonmodular NH2-terminal region, My1, followed by an array of Ig and FnIII domains arranged in the following order: 2Ig (My2-My3)-5FnIII (My4-My8)-5Ig (My9-My13). A developmental splice variant of myomesin, EH-myomesin, contains a unique unstructured ∼100-amino-acid-long Ser/Pro-rich insertion between FnIII domains My6 and My7. The three isoforms share a 40% to 50% overall homology.

Figure 16. Teaching points: The myomesin isoforms contain multiple Ig and FnIII domains, which serve as binding sites for several proteins residing in the thick filament. Specifically, myomesin contains binding sites for the sarcomeric proteins myosin, titin, obscurin, obsl1, and MR1, the metabolic enzyme M-CK, and the sarcolemmal protein dysferlin. Notably, PKA-mediated phosphorylation of myomesin on Ser618 (shown in green) located in the linker region between My4 and My5 inhibits binding to titin. Similarly, phosphorylation of Ser76 (shown in green) in My1 of M-protein precludes binding to LMM.

Figure 17. Teaching points: A limited number of myopathic mutations have been identified to date in MYOM1, whereas there are no known myopathy-causing mutations for MYOM2 and MYOM3. Two missense mutations have been identified in MYOM1, including Glu247Lys residing in My1 and Val1490Ile located in My12 that have been associated with congenital DCM and HCM, respectively. Moreover, aberrant inclusion of MYOM1 exon 17a encoding a 60 to 100-amino-acid-long insert between FnIII domains My6-My7 of myomesin has been implicated in DM1 skeletal myopathy.

Figure 18. Teaching points: Obscurin is the most recently discovered, and the third member of the family of giant sarcomeric proteins expressed in vertebrate striated muscles, along with titin and nebulin. The prototypical obscurin, referred to as obscurin-A (∼720 kDa), contains tandem Ig and FnIII domains followed by an array of signaling motifs. In particular, the NH2-terminus and middle of the molecule consist of 59 Ig and 3 FnIII domains, followed by an IQ rich domain, a SH3 domain, a RhoGEF motif, a PH domain, and a 417-amino acids long COOH-terminal nonmodular region. Obscurin-B (∼870 kDa) is also a giant isoform that shares the same architecture with obscurin-A with the exception of its COOH-terminus that contains two Ser/Thr kinase domains (referred to as Kinase1 and Kinase2) preceded by Ig and Ig/FnIII domains, respectively. Kinase1 and Kinase2 belong to the MLCK subfamily, and can also be expressed as smaller proteins that contain one or both kinase domains, referred to as single (∼55 kDa, only containing Kinase2) and double (∼145 kDa, containing partial Kinase1 and full length Kinase2) kinase isoforms.

Figure 19. Teaching points: Similar to titin, obscurin is a modular protein composed of tandem adhesion and signaling domains which provide binding sites for sarcomeric (MyBP-C, titin, and myomesin), membrane-associated (ankyrins, N-cadherin, and the β1 subunit of NKA-β1), and signaling (RhoA, Ran binding protein 9, and calmodulin) proteins. In addition, a number of binding partners have been identified for the invertebrate obscurin, UNC-89, which are highly conserved among species and include sarcomeric (paramyosin) and signaling (RHO-1, SCPL-1, LIM-9, CPNA-1, Ball, and MASK) proteins as well as E3 ligases (MEL-26).

Figure 20. Teaching points: Little is known about the regulation of obscurins via posttranslational modifications. To date, the only known modification that obscurins undergo is phosphorylation. It is worth noting that both kinase domains present in obscurin-B undergo autophosphorylation in vitro, although the exact sites or the functional significance of these events are currently unknown.

Figure 21. Teaching points: The involvement of obscurins in the development of myopathies has only been recently interrogated leading to the identification of 15 mutations which are linked to different forms of cardiomyopathy including HCM (7), DCM (5), and LVNC (3). Notably, it was recently suggested that OBSCN mutations might be more commonly associated with the pathogenesis of LVNC rather than DCM given their high prevalence in a small cohort of LVNC patients (3/10) versus a large(r) cohort of DCM patients (1/325).


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Article Title: Thick Filament Protein Network, Functions, and Disease Association
 

How to Cite

Li Wang, Janelle Geist, Alyssa Grogan, Li‐Yen R. Hu, Aikaterini Kontrogianni‐Konstantopoulos. Thick Filament Protein Network, Functions, and Disease Association. Compr Physiol 2018, 8: 631-709. doi: 10.1002/cphy.c170023