Anatomy of protein disorder, flexibility and disease-related mutations.
Anatomy of protein disorder, flexibility and disease-related mutations.
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DOI：
10.3389/fmolb.2015.00047
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发表时间：
2015
影响因子：
5
通讯作者：
Fraternali F
中科院分区：
文献类型：
--
作者：
Lu HC;Chung SS;Fornili A;Fraternali F
蛋白质结构信息与人类遗传变异和致病突变的整合对于理解与多态性对蛋白质相互作用和细胞过程的影响相关的分子机制至关重要。我们通过将常见变异和疾病相关的SNPs系统地映射到有序和无序蛋白质区域，研究这些区域中非同义SNPs的发生。我们发现，常见的变异积累在无序的地区，相反，致病的变异显着耗尽无序的地区。致病性和常见SNP的这些不同出现可归因于对结构高度受限区域中的随机突变的负选择。研究致病相关突变的定量效应的新方法应有效地考虑序列变异发生的所有可能背景和相对功能约束。
Integration of protein structural information with human genetic variation and pathogenic mutations is essential to understand molecular mechanisms associated with the effects of polymorphisms on protein interactions and cellular processes. We investigate occurrences of non-synonymous SNPs in ordered and disordered protein regions by systematic mapping of common variants and disease-related SNPs onto these regions. We show that common variants accumulate in disordered regions; conversely pathogenic variants are significantly depleted in disordered regions. These different occurrences of pathogenic and common SNPs can be attributed to a negative selection on random mutations in structurally highly constrained regions. New approaches in the study of quantitative effects of pathogenic-related mutations should effectively account for all the possible contexts and relative functional constraints in which the sequence variation occurs.