Rayment I, Holden H M, Sellers J R, Fananapazir L, Epstein N D
Institute for Enzyme Research, Graduate School, University of Wisconsin, Madison 53705-4098, USA.
Proc Natl Acad Sci U S A. 1995 Apr 25;92(9):3864-8. doi: 10.1073/pnas.92.9.3864.
In 10-30% of hypertrophic cardiomyopathy kindreds, the disease is caused by > 29 missense mutations in the cardiac beta-myosin heavy chain (MYH7) gene. The amino acid sequence similarity between chicken skeletal muscle and human beta-cardiac myosin and the three-dimensional structure of the chicken skeletal muscle myosin head have provided the opportunity to examine the structural consequences of these naturally occurring mutations in human beta-cardiac myosin. This study demonstrates that the mutations are related to distinct structural and functional domains. Twenty-four are clustered around four specific locations in the myosin head that are (i) associated with the actin binding interface, (ii) around the nucleotide binding site, (iii) adjacent to the region that connects the two reactive cysteine residues, and (iv) in close proximity to the interface of the heavy chain with the essential light chain. The remaining five mutations are in the myosin rod. The locations of these mutations provide insight into the way they impair the functioning of this molecular motor and also into the mechanism of energy transduction.
在10% - 30%的肥厚型心肌病家族中，该疾病由心脏β - 肌球蛋白重链（MYH7）基因中超过29个错义突变引起。鸡骨骼肌与人类β - 心脏肌球蛋白之间的氨基酸序列相似性以及鸡骨骼肌肌球蛋白头部的三维结构，为研究这些人类β - 心脏肌球蛋白中自然发生的突变的结构后果提供了机会。这项研究表明，这些突变与不同的结构和功能域相关。其中24个突变聚集在肌球蛋白头部的四个特定位置周围，这些位置分别是：（i）与肌动蛋白结合界面相关；（ii）围绕核苷酸结合位点；（iii）与连接两个反应性半胱氨酸残基的区域相邻；（iv）紧邻重链与必需轻链的界面。其余五个突变位于肌球蛋白杆部。这些突变的位置有助于深入了解它们损害这种分子马达功能的方式，以及能量转导机制。
