Myosin individualized: single nucleotide polymorphisms in energy transduction.
Myosin individualized: single nucleotide polymorphisms in energy transduction.
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DOI：
10.1186/1471-2164-11-172
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发表时间：
2010-03-15
期刊：
影响因子：
4.4
通讯作者：
Ajtai K
中科院分区：
文献类型：
--
作者：
Burghardt TP;Neff KL;Wieben ED;Ajtai K
肌球蛋白在肌球蛋白重链（MHC）的运动域中将ATP自由能转换为机械功。能量转导是肌球蛋白马达的决定性系统特征，其通过按时间顺序协调来执行：活性位点处的ATP水解、肌动蛋白结合位点处的肌动蛋白亲和力调节以及动力冲程的双臂旋转。这些功能由马达结构域内的几个保守的亚结构域执行。单核苷酸多态性（SNP）影响横纹肌、平滑肌和非肌肉组织中表达的许多亚型的MHC序列。这项工作的目的是提供一个合理的使用SNPs作为功能基因组学工具，研究肌球蛋白的结构与功能的关系。特别是发现SNP在保守亚结构域上的分布，并探讨其在能量转导机制中亚结构域稳定性和关键性的意义。一个自动化的程序，识别人类非同义SNP氨基酸错义取代任何MHC基因挖掘NCBI SNP数据库。常规测试了22个编码肌肉和非肌肉亚型的MHC基因，并在运动域中鉴定了89个错义突变位置，其中10个已经与心脏病有关，另外8个缺乏与骨骼MHC亚型的序列同源性，其中晶体学模型可用。发现其余71个SNP替换分布在MHC上，其中22个落在鉴定的功能亚结构域之外，49个在或非常接近肌球蛋白亚结构域，这些亚结构域在能量转导中被分配特定的关键功能。后者包括活性位点、肌动蛋白结合位点、刚性臂和促进它们通讯的区域。大多数MHC亚型在运动域的某处含有SNP。几个功能关键的亚结构域被大量的SNP取代位点渗透，这表明这些结构域通过进化被工程化为过于稳健而不受其他侵入性序列变化的干扰。两个功能性亚结构域是无SNP或相对SNP缺陷的，但含有许多疾病相关突变体。这些亚结构域显然对任何错义取代高度敏感，表明它们未能进化出用于执行其功能的稳健序列范例。
Myosin performs ATP free energy transduction into mechanical work in the motor domain of the myosin heavy chain (MHC). Energy transduction is the definitive systemic feature of the myosin motor performed by coordinating in a time ordered sequence: ATP hydrolysis at the active site, actin affinity modulation at the actin binding site, and the lever-arm rotation of the power stroke. These functions are carried out by several conserved sub-domains within the motor domain. Single nucleotide polymorphisms (SNPs) affect the MHC sequence of many isoforms expressed in striated muscle, smooth muscle, and non-muscle tissue. The purpose of this work is to provide a rationale for using SNPs as a functional genomics tool to investigate structurefunction relationships in myosin. In particular, to discover SNP distribution over the conserved sub-domains and surmise what it implies about sub-domain stability and criticality in the energy transduction mechanism. An automated routine identifying human nonsynonymous SNP amino acid missense substitutions for any MHC gene mined the NCBI SNP data base. The routine tested 22 MHC genes coding muscle and non-muscle isoforms and identified 89 missense mutation positions in the motor domain with 10 already implicated in heart disease and another 8 lacking sequence homology with a skeletal MHC isoform for which a crystallographic model is available. The remaining 71 SNP substitutions were found to be distributed over MHC with 22 falling outside identified functional sub-domains and 49 in or very near to myosin sub-domains assigned specific crucial functions in energy transduction. The latter includes the active site, the actin binding site, the rigid lever-arm, and regions facilitating their communication. Most MHC isoforms contained SNPs somewhere in the motor domain. Several functional-crucial sub-domains are infiltrated by a large number of SNP substitution sites suggesting these domains are engineered by evolution to be too-robust to be disturbed by otherwise intrusive sequence changes. Two functional sub-domains are SNP-free or relatively SNP-deficient but contain many disease implicated mutants. These sub-domains are apparently highly sensitive to any missense substitution suggesting they have failed to evolve a robust sequence paradigm for performing their function.
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