Cargando…

The Primary Causes of Muscle Dysfunction Associated with the Point Mutations in Tpm3.12; Conformational Analysis of Mutant Proteins as a Tool for Classification of Myopathies

Point mutations in genes encoding isoforms of skeletal muscle tropomyosin may cause nemaline myopathy, cap myopathy (Cap), congenital fiber-type disproportion (CFTD), and distal arthrogryposis. The molecular mechanisms of muscle dysfunction in these diseases remain unclear. We studied the effect of...

Descripción completa

Detalles Bibliográficos
Autores principales: Borovikov, Yurii S., Karpicheva, Olga E., Simonyan, Armen O., Avrova, Stanislava V., Rogozovets, Elena A., Sirenko, Vladimir V., Redwood, Charles S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6321504/
https://www.ncbi.nlm.nih.gov/pubmed/30544720
http://dx.doi.org/10.3390/ijms19123975
_version_ 1783385458227544064
author Borovikov, Yurii S.
Karpicheva, Olga E.
Simonyan, Armen O.
Avrova, Stanislava V.
Rogozovets, Elena A.
Sirenko, Vladimir V.
Redwood, Charles S.
author_facet Borovikov, Yurii S.
Karpicheva, Olga E.
Simonyan, Armen O.
Avrova, Stanislava V.
Rogozovets, Elena A.
Sirenko, Vladimir V.
Redwood, Charles S.
author_sort Borovikov, Yurii S.
collection PubMed
description Point mutations in genes encoding isoforms of skeletal muscle tropomyosin may cause nemaline myopathy, cap myopathy (Cap), congenital fiber-type disproportion (CFTD), and distal arthrogryposis. The molecular mechanisms of muscle dysfunction in these diseases remain unclear. We studied the effect of the E173A, R90P, E150A, and A155T myopathy-causing substitutions in γ-tropomyosin (Tpm3.12) on the position of tropomyosin in thin filaments, and the conformational state of actin monomers and myosin heads at different stages of the ATPase cycle using polarized fluorescence microscopy. The E173A, R90P, and E150A mutations produced abnormally large displacement of tropomyosin to the inner domains of actin and an increase in the number of myosin heads in strong-binding state at low and high Ca(2+), which is characteristic of CFTD. On the contrary, the A155T mutation caused a decrease in the amount of such heads at high Ca(2+) which is typical for mutations associated with Cap. An increase in the number of the myosin heads in strong-binding state at low Ca(2+) was observed for all mutations associated with high Ca(2+)-sensitivity. Comparison between the typical conformational changes in mutant proteins associated with different myopathies observed with α-, β-, and γ-tropomyosins demonstrated the possibility of using such changes as tests for identifying the diseases.
format Online
Article
Text
id pubmed-6321504
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-63215042019-01-07 The Primary Causes of Muscle Dysfunction Associated with the Point Mutations in Tpm3.12; Conformational Analysis of Mutant Proteins as a Tool for Classification of Myopathies Borovikov, Yurii S. Karpicheva, Olga E. Simonyan, Armen O. Avrova, Stanislava V. Rogozovets, Elena A. Sirenko, Vladimir V. Redwood, Charles S. Int J Mol Sci Article Point mutations in genes encoding isoforms of skeletal muscle tropomyosin may cause nemaline myopathy, cap myopathy (Cap), congenital fiber-type disproportion (CFTD), and distal arthrogryposis. The molecular mechanisms of muscle dysfunction in these diseases remain unclear. We studied the effect of the E173A, R90P, E150A, and A155T myopathy-causing substitutions in γ-tropomyosin (Tpm3.12) on the position of tropomyosin in thin filaments, and the conformational state of actin monomers and myosin heads at different stages of the ATPase cycle using polarized fluorescence microscopy. The E173A, R90P, and E150A mutations produced abnormally large displacement of tropomyosin to the inner domains of actin and an increase in the number of myosin heads in strong-binding state at low and high Ca(2+), which is characteristic of CFTD. On the contrary, the A155T mutation caused a decrease in the amount of such heads at high Ca(2+) which is typical for mutations associated with Cap. An increase in the number of the myosin heads in strong-binding state at low Ca(2+) was observed for all mutations associated with high Ca(2+)-sensitivity. Comparison between the typical conformational changes in mutant proteins associated with different myopathies observed with α-, β-, and γ-tropomyosins demonstrated the possibility of using such changes as tests for identifying the diseases. MDPI 2018-12-10 /pmc/articles/PMC6321504/ /pubmed/30544720 http://dx.doi.org/10.3390/ijms19123975 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Borovikov, Yurii S.
Karpicheva, Olga E.
Simonyan, Armen O.
Avrova, Stanislava V.
Rogozovets, Elena A.
Sirenko, Vladimir V.
Redwood, Charles S.
The Primary Causes of Muscle Dysfunction Associated with the Point Mutations in Tpm3.12; Conformational Analysis of Mutant Proteins as a Tool for Classification of Myopathies
title The Primary Causes of Muscle Dysfunction Associated with the Point Mutations in Tpm3.12; Conformational Analysis of Mutant Proteins as a Tool for Classification of Myopathies
title_full The Primary Causes of Muscle Dysfunction Associated with the Point Mutations in Tpm3.12; Conformational Analysis of Mutant Proteins as a Tool for Classification of Myopathies
title_fullStr The Primary Causes of Muscle Dysfunction Associated with the Point Mutations in Tpm3.12; Conformational Analysis of Mutant Proteins as a Tool for Classification of Myopathies
title_full_unstemmed The Primary Causes of Muscle Dysfunction Associated with the Point Mutations in Tpm3.12; Conformational Analysis of Mutant Proteins as a Tool for Classification of Myopathies
title_short The Primary Causes of Muscle Dysfunction Associated with the Point Mutations in Tpm3.12; Conformational Analysis of Mutant Proteins as a Tool for Classification of Myopathies
title_sort primary causes of muscle dysfunction associated with the point mutations in tpm3.12; conformational analysis of mutant proteins as a tool for classification of myopathies
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6321504/
https://www.ncbi.nlm.nih.gov/pubmed/30544720
http://dx.doi.org/10.3390/ijms19123975
work_keys_str_mv AT borovikovyuriis theprimarycausesofmuscledysfunctionassociatedwiththepointmutationsintpm312conformationalanalysisofmutantproteinsasatoolforclassificationofmyopathies
AT karpichevaolgae theprimarycausesofmuscledysfunctionassociatedwiththepointmutationsintpm312conformationalanalysisofmutantproteinsasatoolforclassificationofmyopathies
AT simonyanarmeno theprimarycausesofmuscledysfunctionassociatedwiththepointmutationsintpm312conformationalanalysisofmutantproteinsasatoolforclassificationofmyopathies
AT avrovastanislavav theprimarycausesofmuscledysfunctionassociatedwiththepointmutationsintpm312conformationalanalysisofmutantproteinsasatoolforclassificationofmyopathies
AT rogozovetselenaa theprimarycausesofmuscledysfunctionassociatedwiththepointmutationsintpm312conformationalanalysisofmutantproteinsasatoolforclassificationofmyopathies
AT sirenkovladimirv theprimarycausesofmuscledysfunctionassociatedwiththepointmutationsintpm312conformationalanalysisofmutantproteinsasatoolforclassificationofmyopathies
AT redwoodcharless theprimarycausesofmuscledysfunctionassociatedwiththepointmutationsintpm312conformationalanalysisofmutantproteinsasatoolforclassificationofmyopathies
AT borovikovyuriis primarycausesofmuscledysfunctionassociatedwiththepointmutationsintpm312conformationalanalysisofmutantproteinsasatoolforclassificationofmyopathies
AT karpichevaolgae primarycausesofmuscledysfunctionassociatedwiththepointmutationsintpm312conformationalanalysisofmutantproteinsasatoolforclassificationofmyopathies
AT simonyanarmeno primarycausesofmuscledysfunctionassociatedwiththepointmutationsintpm312conformationalanalysisofmutantproteinsasatoolforclassificationofmyopathies
AT avrovastanislavav primarycausesofmuscledysfunctionassociatedwiththepointmutationsintpm312conformationalanalysisofmutantproteinsasatoolforclassificationofmyopathies
AT rogozovetselenaa primarycausesofmuscledysfunctionassociatedwiththepointmutationsintpm312conformationalanalysisofmutantproteinsasatoolforclassificationofmyopathies
AT sirenkovladimirv primarycausesofmuscledysfunctionassociatedwiththepointmutationsintpm312conformationalanalysisofmutantproteinsasatoolforclassificationofmyopathies
AT redwoodcharless primarycausesofmuscledysfunctionassociatedwiththepointmutationsintpm312conformationalanalysisofmutantproteinsasatoolforclassificationofmyopathies