Early-Onset Hypertrophic Cardiomyopathy Mutations Significantly Increase the Velocity, Force, and Actin-Activated ATPase Activity of Human β-Cardiac Myosin
Early-Onset Hypertrophic Cardiomyopathy Mutations Significantly Increase the Velocity, Force, and Actin-Activated ATPase Activity of Human β-Cardiac Myosin
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DOI：
10.1016/j.celrep.2016.11.040
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发表时间：
2016-12-13
期刊：
影响因子：
8.8
通讯作者：
Ruppel, Kathleen M.
中科院分区：
文献类型：
--
作者：
Adhikari, Arjun S.;Kooiker, Kristina B.;Ruppel, Kathleen M.
肥厚性心肌病（HCM）是一种遗传性心血管疾病，500人中有1人患病。HCM的很大比例归因于β -心肌肌球蛋白的突变，这是一种驱动心室收缩的运动蛋白。本研究报道了两种早发性HCM突变D239N和H251N如何影响人β -心肌肌球蛋白的分子生物力学。我们观察到与野生型肌球蛋白相比，肌动蛋白的滑行速度、内在力和atp酶活性显著增加（20%-90%）。此外，对于H251N，我们发现肌球蛋白S1和S2结构域之间的结合亲和力显著降低，这表明这种突变可能通过释放主动马达进一步增加超收缩性。与先前使用人β -心肌肌球蛋白在分子水平上研究的HCM突变不同，早发性HCM突变导致基本生物力学参数的显著较大变化，并表现出明显的超收缩性。
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.