Journal
CELL REPORTS
Volume 17, Issue 11, Pages 2857-2864Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2016.11.040
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Funding
- NIH [GM33289, HL117138, T32 HL094274]
- Lucile Packard CHRI postdoctoral fellowship [UL1 TR001085]
- Stanford ChEM-H Postdocs at the Interface award
- Stanford CVI Postdoctoral award
- American Heart Association [16POST30890005]
- Stanford Spectrum Translational Medicine training grant [TL1RR025742]
- NIGMS [T32GM007276]
- Stanford Bio-X fellowship
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Hypertrophic cardiomyopathy (HCM) is a heritable cardiovascular disorder that affects 1 in 500 people. A significant percentage of HCM is attributed to mutations in beta-cardiac myosin, the motor protein that powers ventricular contraction. This study reports how two early-onset HCM mutations, D239N and H251N, affect the molecular biomechanics of human beta-cardiac myosin. We observed significant increases (20%-90%) in actin gliding velocity, intrinsic force, and ATPase activity in comparison to wild-type myosin. Moreover, for H251N, we found significantly lower binding affinity between the S1 and S2 domains of myosin, suggesting that this mutation may further increase hyper-contractility by releasing active motors. Unlike previous HCM mutations studied at the molecular level using human beta-cardiac myosin, early-onset HCM mutations lead to significantly larger changes in the fundamental biomechanical parameters and show clear hyper-contractility.
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