Departments of Medicine and of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL.
Departments of Medicine and of Physiology, Johns Hopkins University, Baltimore, MD.
J Gen Physiol. 2021 Mar 1;153(3). doi: 10.1085/jgp.202012815.
Reversible Ca2+ binding to troponin is the primary on-off switch of the contractile apparatus of striated muscles, including the heart. Dominant missense mutations in human cardiac troponin genes are among the causes of hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy. Structural understanding of troponin action has recently advanced considerably via electron microscopy and molecular dynamics studies of the thin filament. As a result, it is now possible to examine cardiomyopathy-inducing troponin mutations in thin-filament structural context, and from that to seek new insight into pathogenesis and into the troponin regulatory mechanism. We compiled from consortium reports a representative set of troponin mutation sites whose pathogenicity was determined using standardized clinical genetics criteria. Another set of sites, apparently tolerant of amino acid substitutions, was compiled from the gnomAD v2 database. Pathogenic substitutions occurred predominantly in the areas of troponin that contact actin or tropomyosin, including, but not limited to, two regions of newly proposed structure and long-known implication in cardiomyopathy: the C-terminal third of troponin I and a part of the troponin T N terminus. The pathogenic mutations were located in troponin regions that prevent contraction under low Ca2+ concentration conditions. These regions contribute to Ca2+-regulated steric hindrance of myosin by the combined effects of troponin and tropomyosin. Loss-of-function mutations within these parts of troponin result in loss of inhibition, consistent with the hypercontractile phenotype characteristic of HCM. Notably, pathogenic mutations are absent in our dataset from the Ca2+-binding, activation-producing troponin C (TnC) N-lobe, which controls contraction by a multi-faceted mechanism. Apparently benign mutations are also diminished in the TnC N-lobe, suggesting mutations are poorly tolerated in that critical domain.
肌钙蛋白与钙离子的可逆结合是横纹肌（包括心脏）收缩装置的主要开启和关闭开关。人类心肌肌钙蛋白基因中的显性错义突变是肥厚型心肌病（HCM）和扩张型心肌病的病因之一。通过对细肌丝的电子显微镜和分子动力学研究，最近对肌钙蛋白的作用结构有了相当大的了解。因此，现在可以在细肌丝结构背景下检查引起心肌病的肌钙蛋白突变，并从中寻找对发病机制和肌钙蛋白调节机制的新见解。我们从联盟报告中编译了一组有代表性的肌钙蛋白突变位点，这些突变位点的致病性是使用标准化的临床遗传学标准来确定的。从 gnomAD v2 数据库中编译了另一组显然耐受氨基酸取代的位点。致病性取代主要发生在肌钙蛋白与肌动蛋白或原肌球蛋白相互作用的区域，包括但不限于两个新提出的结构区域和长期以来与心肌病有关的区域：肌钙蛋白 I 的 C 端三分之一和肌钙蛋白 T N 端的一部分。致病性突变位于肌钙蛋白的区域，在低 Ca2+浓度条件下阻止收缩。这些区域通过肌钙蛋白和原肌球蛋白的综合作用，对肌球蛋白的 Ca2+调节空间位阻起作用。这些肌钙蛋白区域内的功能丧失突变导致抑制丧失，与 HCM 特有的高收缩表型一致。值得注意的是，我们的数据集没有 Ca2+结合、产生激活的肌钙蛋白 C（TnC）N 端的致病性突变，该区域通过多方面的机制控制收缩。显然，良性突变在 TnC N 端也减少了，这表明在那个关键区域突变不易耐受。
