文章基本信息

标题：Decoding disease-causing mechanisms of missense mutations from supramolecular structures
本地全文：下载
作者：Atsushi Hijikata ; Toshiyuki Tsuji ; Masafumi Shionyu 等
期刊名称：Scientific Reports
电子版ISSN：2045-2322
出版年度：2017
卷号：7
期号：1
DOI：10.1038/s41598-017-08902-1
语种：English
出版社：Springer Nature
摘要：The inheritance modes of pathogenic missense mutations are known to be highly associated with protein structures; recessive mutations are mainly observed in the buried region of protein structures, whereas dominant mutations are significantly enriched in the interfaces of molecular interactions. However, the differences in phenotypic impacts among various dominant mutations observed in individuals are not fully understood. In the present study, the functional effects of pathogenic missense mutations on three-dimensional macromolecular complex structures were explored in terms of dominant mutation types, namely, haploinsufficiency, dominant-negative, or toxic gain-of-function. The major types of dominant mutation were significantly associated with the different types of molecular interactions, such as protein-DNA, homo-oligomerization, or intramolecular domain-domain interactions, affected by mutations. The dominant-negative mutations were biased toward molecular interfaces for cognate protein or DNA. The haploinsufficiency mutations were enriched on the DNA interfaces. The gain-of-function mutations were localized to domain-domain interfaces. Our results demonstrate a novel use of macromolecular complex structures for predicting the disease-causing mechanisms through inheritance modes.