The biochemically defined super relaxed state of myosin-A paradox.

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  • Additional Information
    • Source:
      Publisher: Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Country of Publication: United States NLM ID: 2985121R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1083-351X (Electronic) Linking ISSN: 00219258 NLM ISO Abbreviation: J Biol Chem Subsets: MEDLINE
    • Publication Information:
      Publication: 2021- : [New York, NY] : Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology
      Original Publication: Baltimore, MD : American Society for Biochemistry and Molecular Biology
    • Subject Terms:
      Adenosine Triphosphate*/analogs & derivatives ; Adenosine Triphosphate*/metabolism ; Enzyme Assays*/methods ; Enzyme Assays*/standards ; Nonmuscle Myosin Type IIA*/chemistry ; Nonmuscle Myosin Type IIA*/metabolism ; ortho-Aminobenzoates*/metabolism ; Swine*; Animals ; Adenosine Triphosphatases/antagonists & inhibitors ; Adenosine Triphosphatases/metabolism ; Amino Acid Motifs ; Benzylamines/pharmacology ; Heart Ventricles/drug effects ; Heart Ventricles/enzymology ; Heart Ventricles/metabolism ; Myocardial Contraction ; Myosin Subfragments/chemistry ; Myosin Subfragments/metabolism ; Uracil/analogs & derivatives ; Uracil/pharmacology
    • Abstract:
      The biochemical SRX (super-relaxed) state of myosin has been defined as a low ATPase activity state. This state can conserve energy when the myosin is not recruited for muscle contraction. The SRX state has been correlated with a structurally defined ordered (versus disordered) state of muscle thick filaments. The two states may be linked via a common interacting head motif (IHM) where the two heads of heavy meromyosin (HMM), or myosin, fold back onto each other and form additional contacts with S2 and the thick filament. Experimental observations of the SRX, IHM, and the ordered form of thick filaments, however, do not always agree, and result in a series of unresolved paradoxes. To address these paradoxes, we have reexamined the biochemical measurements of the SRX state for porcine cardiac HMM. In our hands, the commonly employed mantATP displacement assay was unable to quantify the population of the SRX state with all data fitting very well by a single exponential. We further show that mavacamten inhibits the basal ATPases of both porcine ventricle HMM and S1 (K i , 0.32 and 1.76 μM respectively) while dATP activates HMM cooperatively without any evidence of an SRX state. A combination of our experimental observations and theories suggests that the displacement of mantATP in purified proteins is not a reliable assay to quantify the SRX population. This means that while the structurally defined IHM and ordered thick filaments clearly exist, great care must be employed when using the mantATP displacement assay.
      Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article.
      (Crown Copyright © 2023. Published by Elsevier Inc. All rights reserved.)
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    • Grant Information:
      RM1 GM131981 United States GM NIGMS NIH HHS; R01 HL157169 United States HL NHLBI NIH HHS; P30 AR074990 United States AR NIAMS NIH HHS; T32 EB032787 United States EB NIBIB NIH HHS; R01 HL128368 United States HL NHLBI NIH HHS
    • Contributed Indexing:
      Keywords: ATPase; cardiomyopathy; deoxyATP; mavacamten; myosin regulation; super-relaxed state; thick filament regulation
    • Accession Number:
      85287-56-5 (3'-O-(N-methylanthraniloyl) ATP)
      EC 3.6.1.- (Adenosine Triphosphatases)
      8L70Q75FXE (Adenosine Triphosphate)
      0 (Benzylamines)
      0 (MYK-461)
      0 (Myosin Subfragments)
      EC 3.6.1.- (Nonmuscle Myosin Type IIA)
      0 (ortho-Aminobenzoates)
      56HH86ZVCT (Uracil)
    • Publication Date:
      Date Created: 20231216 Date Completed: 20240209 Latest Revision: 20241023
    • Publication Date:
      20241023
    • Accession Number:
      PMC10819765
    • Accession Number:
      10.1016/j.jbc.2023.105565
    • Accession Number:
      38103642