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
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Publicado: Nature Portfolio 2017
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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
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