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TitleEffects of myosin variants on interacting-heads motif explain distinct hypertrophic and dilated cardiomyopathy phenotypes.
Journal, issue, pagesElife, Vol. 6, Year 2017
Publish dateJun 13, 2017
AuthorsLorenzo Alamo / James S Ware / Antonio Pinto / Richard E Gillilan / Jonathan G Seidman / Christine E Seidman / Raúl Padrón /
PubMed AbstractCardiac β-myosin variants cause hypertrophic (HCM) or dilated (DCM) cardiomyopathy by disrupting sarcomere contraction and relaxation. The locations of variants on isolated myosin head structures ...Cardiac β-myosin variants cause hypertrophic (HCM) or dilated (DCM) cardiomyopathy by disrupting sarcomere contraction and relaxation. The locations of variants on isolated myosin head structures predict contractility effects but not the prominent relaxation and energetic deficits that characterize HCM. During relaxation, pairs of myosins form interacting-heads motif (IHM) structures that with other sarcomere proteins establish an energy-saving, super-relaxed (SRX) state. Using a human β-cardiac myosin IHM quasi-atomic model, we defined interactions sites between adjacent myosin heads and associated protein partners, and then analyzed rare variants from 6112 HCM and 1315 DCM patients and 33,370 ExAC controls. HCM variants, 72% that changed electrostatic charges, disproportionately altered IHM interaction residues (expected 23%; HCM 54%, p=2.6×10; DCM 26%, p=0.66; controls 20%, p=0.23). HCM variant locations predict impaired IHM formation and stability, and attenuation of the SRX state - accounting for altered contractility, reduced diastolic relaxation, and increased energy consumption, that fully characterizes HCM pathogenesis.
External linksElife / PubMed:28606303 / PubMed Central
MethodsEM (single particle)
Resolution20 Å
Structure data

PDB-5tby:
HUMAN BETA CARDIAC HEAVY MEROMYOSIN INTERACTING-HEADS MOTIF OBTAINED BY HOMOLOGY MODELING (USING SWISS-MODEL) OF HUMAN SEQUENCE FROM APHONOPELMA HOMOLOGY MODEL (PDB-3JBH), RIGIDLY FITTED TO HUMAN BETA-CARDIAC NEGATIVELY STAINED THICK FILAMENT 3D-RECONSTRUCTION (EMD-2240)
Method: ELECTRON MICROSCOPY / Resolution: 20 Å

Source
  • homo sapiens (human)
KeywordsCONTRACTILE PROTEIN / CONTRACTILE PROTEIN Hypertrophic or dilated cardiomyopathy beta-cardiac myosin II Myosin interacting-heads motif

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