Conformational plasticity and evolutionary analysis of the myotilin tandem Ig domains

Abstract Myotilin is a component of the sarcomere where it plays an important role in organisation and maintenance of Z-disk integrity. This involves direct binding to F-actin and filamin C, a function mediated by its Ig domain pair. While the structures of these two individual domains are known, in...

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Autores principales:	Vid Puž, Miha Pavšič, Brigita Lenarčič, Kristina Djinović-Carugo
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/c9ab95b6f7574c8ab9cb2d8daa190733
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spelling	oai:doaj.org-article:c9ab95b6f7574c8ab9cb2d8daa1907332021-12-02T11:52:28ZConformational plasticity and evolutionary analysis of the myotilin tandem Ig domains10.1038/s41598-017-03323-62045-2322https://doaj.org/article/c9ab95b6f7574c8ab9cb2d8daa1907332017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-03323-6https://doaj.org/toc/2045-2322Abstract Myotilin is a component of the sarcomere where it plays an important role in organisation and maintenance of Z-disk integrity. This involves direct binding to F-actin and filamin C, a function mediated by its Ig domain pair. While the structures of these two individual domains are known, information about their relative orientation and flexibility remains limited. We set on to characterise the Ig domain pair of myotilin with emphasis on its molecular structure, dynamics and phylogeny. First, sequence conservation analysis of myotilin shed light on the molecular basis of myotilinopathies and revealed several motifs in Ig domains found also in I-band proteins. In particular, a highly conserved Glu344 mapping to Ig domain linker, was identified as a critical component of the inter-domain hinge mechanism. Next, SAXS and molecular dynamics revealed that Ig domain pair exists as a multi-conformation species with dynamic exchange between extended and compact orientations. Mutation of AKE motif to AAA further confirmed its impact on inter-domain flexibility. We hypothesise that the conformational plasticity of the Ig domain pair in its unbound form is part of the binding partner recognition mechanism.Vid PužMiha PavšičBrigita LenarčičKristina Djinović-CarugoNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-12 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Vid Puž Miha Pavšič Brigita Lenarčič Kristina Djinović-Carugo Conformational plasticity and evolutionary analysis of the myotilin tandem Ig domains
description	Abstract Myotilin is a component of the sarcomere where it plays an important role in organisation and maintenance of Z-disk integrity. This involves direct binding to F-actin and filamin C, a function mediated by its Ig domain pair. While the structures of these two individual domains are known, information about their relative orientation and flexibility remains limited. We set on to characterise the Ig domain pair of myotilin with emphasis on its molecular structure, dynamics and phylogeny. First, sequence conservation analysis of myotilin shed light on the molecular basis of myotilinopathies and revealed several motifs in Ig domains found also in I-band proteins. In particular, a highly conserved Glu344 mapping to Ig domain linker, was identified as a critical component of the inter-domain hinge mechanism. Next, SAXS and molecular dynamics revealed that Ig domain pair exists as a multi-conformation species with dynamic exchange between extended and compact orientations. Mutation of AKE motif to AAA further confirmed its impact on inter-domain flexibility. We hypothesise that the conformational plasticity of the Ig domain pair in its unbound form is part of the binding partner recognition mechanism.
format	article
author	Vid Puž Miha Pavšič Brigita Lenarčič Kristina Djinović-Carugo
author_facet	Vid Puž Miha Pavšič Brigita Lenarčič Kristina Djinović-Carugo
author_sort	Vid Puž
title	Conformational plasticity and evolutionary analysis of the myotilin tandem Ig domains
title_short	Conformational plasticity and evolutionary analysis of the myotilin tandem Ig domains
title_full	Conformational plasticity and evolutionary analysis of the myotilin tandem Ig domains
title_fullStr	Conformational plasticity and evolutionary analysis of the myotilin tandem Ig domains
title_full_unstemmed	Conformational plasticity and evolutionary analysis of the myotilin tandem Ig domains
title_sort	conformational plasticity and evolutionary analysis of the myotilin tandem ig domains
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/c9ab95b6f7574c8ab9cb2d8daa190733
work_keys_str_mv	AT vidpuz conformationalplasticityandevolutionaryanalysisofthemyotilintandemigdomains AT mihapavsic conformationalplasticityandevolutionaryanalysisofthemyotilintandemigdomains AT brigitalenarcic conformationalplasticityandevolutionaryanalysisofthemyotilintandemigdomains AT kristinadjinoviccarugo conformationalplasticityandevolutionaryanalysisofthemyotilintandemigdomains
_version_	1718395069924376576

Conformational plasticity and evolutionary analysis of the myotilin tandem Ig domains

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