The structural OFF and ON states of myosin can be decoupled from the biochemical super- and disordered-relaxed states

Jani, Vivek P.; Song, Taejeong; Gao, Chengqian; Gong, Henry; Sadayappan, Sakthivel; Kass, David A.; Irving, Thomas C.; Ma, Weikang; Bahar, ed., Ivet

doi:10.1093/pnasnexus/pgae039

The structural OFF and ON states of myosin can be decoupled from the biochemical super- and disordered-relaxed states

Journal Article · Tue Jan 30 00:00:00 EST 2024 · PNAS Nexus

DOI:https://doi.org/10.1093/pnasnexus/pgae039· OSTI ID:2290444

; ; ; Gong, Henry; ; ; ; ; Bahar, ed., Ivet

Abstract

There is a growing awareness that both thick-filament and classical thin-filament regulations play central roles in modulating muscle contraction. Myosin ATPase assays have demonstrated that under relaxed conditions, myosin may reside either in a high-energy-consuming disordered-relaxed (DRX) state available for binding actin to generate force or in an energy-sparing super-relaxed (SRX) state unavailable for actin binding. X-ray diffraction studies have shown that the majority of myosin heads are in a quasi-helically ordered OFF state in a resting muscle and that this helical ordering is lost when myosin heads are turned ON for contraction. It has been assumed that myosin heads in SRX and DRX states are equivalent to the OFF and ON states, respectively, and the terms have been used interchangeably. In this study, we use X-ray diffraction and ATP turnover assays to track the structural and biochemical transitions of myosin heads, respectively, induced with either omecamtiv mecarbil (OM) or piperine in relaxed porcine myocardium. We find that while OM and piperine induce dramatic shifts of myosin heads from the OFF to the ON state, there are no appreciable changes in the population of myosin heads in the SRX and DRX states in both unloaded and loaded preparations. Our results show that biochemically defined SRX and DRX can be decoupled from structurally defined OFF and ON states. In summary, while SRX/DRX and OFF/ON transitions can be correlated in some cases, these two phenomena are measured using different approaches, reflect different properties of the thick filament, and should be investigated and interpreted separately.

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Sponsoring Organization:: USDOE

OSTI ID:: 2290444

Journal Information:: PNAS Nexus, Journal Name: PNAS Nexus Journal Issue: 2 Vol. 3; ISSN 2752-6542

Publisher:: Oxford University PressCopyright Statement

Country of Publication:: United States

Language:: English

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