Mutations in β-myosin S2 that cause familial hypertrophic cardiomyopathy (FHC) abolish the interaction with the regulatory domain of myosin-binding protein-C
Mutations in β-myosin S2 that cause familial hypertrophic cardiomyopathy (FHC) abolish the interaction with the regulatory domain of myosin-binding protein-C
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DOI：
10.1006/jmbi.1998.2522
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发表时间：
1999-02-26
影响因子：
5.6
通讯作者：
Gautel, M
中科院分区：
文献类型：
--
作者：
Gruen, M;Gautel, M
横纹肌的肌球蛋白丝包含一个神秘的肌球蛋白结合蛋白（MyBP）家族，MyBP-C和MyBP-H。细胞内免疫球蛋白超家族的这些模块蛋白在其N末端附近含有独特的结构域。心肌MyBP-C的N-末端结构域MyBP-C基序含有额外的磷酸化位点，并且可以以磷酸化依赖的方式调节收缩。相反，C末端，结合轻肌球蛋白的肌球蛋白杆的部分，这个域的相互作用是未知的。我们证明，片段的MyBP-C包含MyBP-C基序定位于肌节A带在心肌细胞和分离的肌原纤维，而不影响肌节结构。MyBP-C基序的结合位点位于肌球蛋白杆的S2段的N-末端126个残基。在这个区域，β-肌球蛋白的几个突变与FHC相关;然而，它们的分子意义仍然不清楚。我们发现β-肌球蛋白S2中两个代表性的FHC突变，R870 H和E924 K，显著降低了MyBP-C结合（R870 H的K（d）约为60 μ M，而野生型的K（d）约为5 μ M），降至检测不到的水平（E924 K）。这些突变不影响肌球蛋白的卷曲螺旋结构。我们认为MyBP-C的调节功能是通过与S2的相互作用介导的，β-肌球蛋白S2的突变可能通过改变与MyBP-C的相互作用而起作用。(C)北京：科学出版社.
The myosin filaments of striated muscle contain a family of enigmatic myosin-binding proteins (MyBP), MyBP-C and MyBP-H. These modular proteins of the intracellular immunoglobulin superfamily contain unique domains near their N termini. The N-terminal domain of cardiac MyBP-C, the MyBP-C motif, contains additional phosphorylation sites and may regulate contraction in a phosphorylation dependent way. In contrast to the C terminus, which binds to the light meromyosin portion of the myosin rod, the interactions of this domain are unknown. We demonstrate that fragments of MyBP-C containing the MyBP-C motif localise to the sarcomeric A-band in cardiomyocytes and isolated myofibrils, without affecting sarcomere structure. The binding site for the MyBP-C motif resides in the N-terminal 126 residues of the S2 segment of the myosin rod. In this region, several mutations in beta-myosin are associated with FHC; however, their molecular implications remained unclear. We show that two representative FHC mutations in beta-myosin S2, R870H and E924K, drastically reduce MyBP-C binding (K(d) approximate to 60 mu M for R870H compared with a K(d) of approximate to 5 mu M for the wild-type) down to undetectable levels (E924K). These mutations do not affect the coiled-coil structure of myosin. We suggest that the regulatory function of MyBP-C is mediated by the interaction with S2, and that mutations in beta-myosin S2 may act by altering the interactions with MyBP-C. (C) 1999 Academic Press.