Decoding disease-causing mechanisms of missense mutations from supramolecular structures

Abstract 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 interact...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Atsushi Hijikata, Toshiyuki Tsuji, Masafumi Shionyu, Tsuyoshi Shirai
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/f36a28c1ef944b89891155264aaa0f6e
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:f36a28c1ef944b89891155264aaa0f6e
record_format	dspace
spelling	oai:doaj.org-article:f36a28c1ef944b89891155264aaa0f6e2021-12-02T12:31:46ZDecoding disease-causing mechanisms of missense mutations from supramolecular structures10.1038/s41598-017-08902-12045-2322https://doaj.org/article/f36a28c1ef944b89891155264aaa0f6e2017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-08902-1https://doaj.org/toc/2045-2322Abstract 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.Atsushi HijikataToshiyuki TsujiMasafumi ShionyuTsuyoshi ShiraiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-8 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Atsushi Hijikata Toshiyuki Tsuji Masafumi Shionyu Tsuyoshi Shirai Decoding disease-causing mechanisms of missense mutations from supramolecular structures
description	Abstract 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.
format	article
author	Atsushi Hijikata Toshiyuki Tsuji Masafumi Shionyu Tsuyoshi Shirai
author_facet	Atsushi Hijikata Toshiyuki Tsuji Masafumi Shionyu Tsuyoshi Shirai
author_sort	Atsushi Hijikata
title	Decoding disease-causing mechanisms of missense mutations from supramolecular structures
title_short	Decoding disease-causing mechanisms of missense mutations from supramolecular structures
title_full	Decoding disease-causing mechanisms of missense mutations from supramolecular structures
title_fullStr	Decoding disease-causing mechanisms of missense mutations from supramolecular structures
title_full_unstemmed	Decoding disease-causing mechanisms of missense mutations from supramolecular structures
title_sort	decoding disease-causing mechanisms of missense mutations from supramolecular structures
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/f36a28c1ef944b89891155264aaa0f6e
work_keys_str_mv	AT atsushihijikata decodingdiseasecausingmechanismsofmissensemutationsfromsupramolecularstructures AT toshiyukitsuji decodingdiseasecausingmechanismsofmissensemutationsfromsupramolecularstructures AT masafumishionyu decodingdiseasecausingmechanismsofmissensemutationsfromsupramolecularstructures AT tsuyoshishirai decodingdiseasecausingmechanismsofmissensemutationsfromsupramolecularstructures
_version_	1718394313646276608

Decoding disease-causing mechanisms of missense mutations from supramolecular structures

Ejemplares similares