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TitleStructure of mavacamten-free human cardiac thick filaments within the sarcomere by cryoelectron tomography.
Journal, issue, pagesProc Natl Acad Sci U S A, Vol. 121, Issue 9, Page e2311883121, Year 2024
Publish dateFeb 27, 2024
AuthorsLiang Chen / Jun Liu / Hosna Rastegarpouyani / Paul M L Janssen / Jose R Pinto / Kenneth A Taylor /
PubMed AbstractHeart muscle has the unique property that it can never rest; all cardiomyocytes contract with each heartbeat which requires a complex control mechanism to regulate cardiac output to physiological ...Heart muscle has the unique property that it can never rest; all cardiomyocytes contract with each heartbeat which requires a complex control mechanism to regulate cardiac output to physiological requirements. Changes in calcium concentration regulate the thin filament activation. A separate but linked mechanism regulates the thick filament activation, which frees sufficient myosin heads to bind the thin filament, thereby producing the required force. Thick filaments contain additional nonmyosin proteins, myosin-binding protein C and titin, the latter being the protein that transmits applied tension to the thick filament. How these three proteins interact to control thick filament activation is poorly understood. Here, we show using 3-D image reconstruction of frozen-hydrated human cardiac muscle myofibrils lacking exogenous drugs that the thick filament is structured to provide three levels of myosin activation corresponding to the three crowns of myosin heads in each 429Å repeat. In one crown, the myosin heads are almost completely activated and disordered. In another crown, many myosin heads are inactive, ordered into a structure called the interacting heads motif. At the third crown, the myosin heads are ordered into the interacting heads motif, but the stability of that motif is affected by myosin-binding protein C. We think that this hierarchy of control explains many of the effects of length-dependent activation as well as stretch activation in cardiac muscle control.
External linksProc Natl Acad Sci U S A / PubMed:38386705 / PubMed Central
MethodsEM (subtomogram averaging)
Resolution16.5 - 26.4 Å
Structure data

EMDB-40468: In situ human cardiac thick filament in the relaxed state
Method: EM (subtomogram averaging) / Resolution: 16.5 Å

EMDB-40471: Human cardiac interacting heads motif (IHM-C) in complete form
Method: EM (subtomogram averaging) / Resolution: 20.3 Å

EMDB-40475: Human cardiac interacting heads motif (IHM-C) in semi form
Method: EM (subtomogram averaging) / Resolution: 22.7 Å

EMDB-40476: Human cardiac interacting heads motif (IHM-S)
Method: EM (subtomogram averaging) / Resolution: 21.7 Å

EMDB-40478: Human cardiac interacting heads motif (IHM-D) in semi form
Method: EM (subtomogram averaging) / Resolution: 26.4 Å

Source
  • Homo sapiens (human)

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