"Momentum" Membrane Protein Bioinformatics Research Group, Institute of Enzymology, RCNS, HAS, PO-Box 7, Budapest H-1518, Hungary.
"Momentum" MTA-ELTE Bioinformatics Research Group, Department of Biochemistry, Eötvös Loránd University, Pázmány Péter sétány 1/c, Budapest H-1117, Hungary.
J Mol Biol. 2018 Dec 7;430(24):4955-4970. doi: 10.1016/j.jmb.2018.10.005. Epub 2018 Oct 22.
Advancements in sequencing in the past decades enabled not only the determination of the human proteome but also the identification of a large number of genetic variations in the human population. The phenotypic effects of these mutations range from neutral for polymorphisms to severe for some somatic mutations. Disease-causing germline mutations (DCMs) represent a special and largely understudied class with relatively weak phenotypes. While for somatic mutations their effect on protein structure and regulation has been extensively studied in select cases, for germline mutations, this information is currently largely missing. In this analysis, a large amount of DCMs were analyzed and contrasted to polymorphisms from a structural point of view. Our results delineate the characteristic features of DCMs starting at the global level of partitioning proteins into globular, disordered and transmembrane classes, moving toward smaller structural units describing secondary structure elements and molecular surfaces, reaching down to the smallest structural entity, post-translational modifications. We show how these structural entities influence the emergence and possible phenotypic effects of DCMs.
过去几十年中测序技术的进步不仅使人类蛋白质组的测定成为可能，而且还鉴定了人类群体中大量的遗传变异。这些突变的表型效应范围从多态性的中性到一些体细胞突变的严重。致病种系突变 (DCMs) 是一类特殊的、研究相对较少的突变，其表型相对较弱。虽然在某些情况下，体细胞突变对蛋白质结构和调节的影响已经得到了广泛的研究，但对于种系突变，目前这方面的信息还很缺乏。在这项分析中，从结构角度分析了大量的 DCMs，并与多态性进行了对比。我们的结果从全局水平上将蛋白质划分为球状、无序和跨膜类开始，描述了二级结构元素和分子表面的较小结构单元，一直到最小的结构实体，即翻译后修饰，描绘了 DCMs 的特征。我们展示了这些结构实体如何影响 DCMs 的出现和可能的表型效应。
