K336I mutant actin alters the structure of neighbouring protomers in filaments and reduces affinity for actin-binding proteins

Abstract Mutation of the Lys-336 residue of actin to Ile (K336I) or Asp (K336E) causes congenital myopathy. To understand the effect of this mutation on the function of actin filaments and gain insight into the mechanism of disease onset, we prepared and biochemically characterised K336I mutant acti...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Nobuhisa Umeki, Keitaro Shibata, Taro Q. P. Noguchi, Keiko Hirose, Yasushi Sako, Taro Q. P. Uyeda
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2019
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/47043d6050ef477ba9bafdcf76f063b1
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:47043d6050ef477ba9bafdcf76f063b1
record_format	dspace
spelling	oai:doaj.org-article:47043d6050ef477ba9bafdcf76f063b12021-12-02T15:09:43ZK336I mutant actin alters the structure of neighbouring protomers in filaments and reduces affinity for actin-binding proteins10.1038/s41598-019-41795-w2045-2322https://doaj.org/article/47043d6050ef477ba9bafdcf76f063b12019-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-019-41795-whttps://doaj.org/toc/2045-2322Abstract Mutation of the Lys-336 residue of actin to Ile (K336I) or Asp (K336E) causes congenital myopathy. To understand the effect of this mutation on the function of actin filaments and gain insight into the mechanism of disease onset, we prepared and biochemically characterised K336I mutant actin from Dictyostelium discoideum. Subtilisin cleavage assays revealed that the structure of the DNase-I binding loop (D-loop) of monomeric K336I actin, which would face the adjacent actin-protomer in filaments, differed from that of wild type (WT) actin. Although K336I actin underwent normal salt-dependent reversible polymerisation and formed apparently normal filaments, interactions of K336I filaments with alpha-actinin, myosin II, and cofilin were disrupted. Furthermore, co-filaments of K336I and WT actins also exhibited abnormal interactions with cofilin, implying that K336I actin altered the structure of the neighbouring WT actin protomers such that interaction between cofilin and the WT actin protomers was prevented. We speculate that disruption of the interactions between co-filaments and actin-binding proteins is the primary reason why the K336I mutation induces muscle disease in a dominant fashion.Nobuhisa UmekiKeitaro ShibataTaro Q. P. NoguchiKeiko HiroseYasushi SakoTaro Q. P. UyedaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 9, Iss 1, Pp 1-10 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Nobuhisa Umeki Keitaro Shibata Taro Q. P. Noguchi Keiko Hirose Yasushi Sako Taro Q. P. Uyeda K336I mutant actin alters the structure of neighbouring protomers in filaments and reduces affinity for actin-binding proteins
description	Abstract Mutation of the Lys-336 residue of actin to Ile (K336I) or Asp (K336E) causes congenital myopathy. To understand the effect of this mutation on the function of actin filaments and gain insight into the mechanism of disease onset, we prepared and biochemically characterised K336I mutant actin from Dictyostelium discoideum. Subtilisin cleavage assays revealed that the structure of the DNase-I binding loop (D-loop) of monomeric K336I actin, which would face the adjacent actin-protomer in filaments, differed from that of wild type (WT) actin. Although K336I actin underwent normal salt-dependent reversible polymerisation and formed apparently normal filaments, interactions of K336I filaments with alpha-actinin, myosin II, and cofilin were disrupted. Furthermore, co-filaments of K336I and WT actins also exhibited abnormal interactions with cofilin, implying that K336I actin altered the structure of the neighbouring WT actin protomers such that interaction between cofilin and the WT actin protomers was prevented. We speculate that disruption of the interactions between co-filaments and actin-binding proteins is the primary reason why the K336I mutation induces muscle disease in a dominant fashion.
format	article
author	Nobuhisa Umeki Keitaro Shibata Taro Q. P. Noguchi Keiko Hirose Yasushi Sako Taro Q. P. Uyeda
author_facet	Nobuhisa Umeki Keitaro Shibata Taro Q. P. Noguchi Keiko Hirose Yasushi Sako Taro Q. P. Uyeda
author_sort	Nobuhisa Umeki
title	K336I mutant actin alters the structure of neighbouring protomers in filaments and reduces affinity for actin-binding proteins
title_short	K336I mutant actin alters the structure of neighbouring protomers in filaments and reduces affinity for actin-binding proteins
title_full	K336I mutant actin alters the structure of neighbouring protomers in filaments and reduces affinity for actin-binding proteins
title_fullStr	K336I mutant actin alters the structure of neighbouring protomers in filaments and reduces affinity for actin-binding proteins
title_full_unstemmed	K336I mutant actin alters the structure of neighbouring protomers in filaments and reduces affinity for actin-binding proteins
title_sort	k336i mutant actin alters the structure of neighbouring protomers in filaments and reduces affinity for actin-binding proteins
publisher	Nature Portfolio
publishDate	2019
url	https://doaj.org/article/47043d6050ef477ba9bafdcf76f063b1
work_keys_str_mv	AT nobuhisaumeki k336imutantactinaltersthestructureofneighbouringprotomersinfilamentsandreducesaffinityforactinbindingproteins AT keitaroshibata k336imutantactinaltersthestructureofneighbouringprotomersinfilamentsandreducesaffinityforactinbindingproteins AT taroqpnoguchi k336imutantactinaltersthestructureofneighbouringprotomersinfilamentsandreducesaffinityforactinbindingproteins AT keikohirose k336imutantactinaltersthestructureofneighbouringprotomersinfilamentsandreducesaffinityforactinbindingproteins AT yasushisako k336imutantactinaltersthestructureofneighbouringprotomersinfilamentsandreducesaffinityforactinbindingproteins AT taroqpuyeda k336imutantactinaltersthestructureofneighbouringprotomersinfilamentsandreducesaffinityforactinbindingproteins
_version_	1718387749408473088

K336I mutant actin alters the structure of neighbouring protomers in filaments and reduces affinity for actin-binding proteins

Ejemplares similares