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First published online 13 May 2008
doi: 10.1242/jcs.028019

This Article Figures Only Full Text Full Text (PDF) Supplementary Material All Versions of this Article: jcs.028019v1 121/11/1841    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Related articles in JCS Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Google Scholar Articles by Fukuzawa, A. Articles by Gautel, M. PubMed PubMed Citation Articles by Fukuzawa, A. Articles by Gautel, M.

Interactions with titin and myomesin target obscurin and obscurin-like 1 to the M-band – implications for hereditary myopathies

Atsushi Fukuzawa^1,*, Stephan Lange^1,*,, Mark Holt¹, Anna Vihola², Virginie Carmignac^3,4,, Ana Ferreiro^3,4, Bjarne Udd^2,5 and Mathias Gautel^1,¶

¹ King's College London, The Randall Division for Cell and Molecular Biophysics, and Cardiovascular Division, New Hunt's House, London SE1 1UL, UK
² The Folkhälsan Institute of Genetics and Department of Medical Genetics, University of Helsinki, Biomedicum, Helsinki, Finland
³ INSERM, U582, Institut de Myologie, Paris, France
⁴ Université Pierre et Marie Curie, Paris, France
⁵ Department of Neurology, Vasa Central Hospital, Vasa, Finland

^¶ Author for correspondence (e-mail: mathias.gautel{at}kcl.ac.uk)

Accepted 11 March 2008

Obscurin, a giant modular muscle protein implicated in G-protein and protein-kinase signalling, can localize to both sarcomeric Z-disks and M-bands. Interaction of obscurin with the Z-disk is mediated by Z-disk titin. Here, we unravel the molecular basis for the unusual localization of obscurin, a Z-disk-associated protein, to the M-band, where its invertebrate analogue UNC-89 is also localized. The first three domains of the N-terminus of obscurin bind to the most C-terminal domain of M-band titin, as well as to the M-band protein myomesin. Both proteins also interact with the N-terminal domains of obscurin-like 1 (Obsl1), a small homologue of obscurin. Downregulation of myomesin by siRNA interference disrupts obscurin–M-band integration in neonatal cardiomyocytes, as does overexpression of the binding sites on either myomesin, obscurin or Obsl1. Furthermore, all titin mutations that have been linked to limb-girdle muscular dystrophy 2J (LGMD2J) or Salih myopathy weaken or abrogate titin-obscurin and titin-Obsl1 binding, and lead to obscurin mislocalization, suggesting that interference with the interaction of these proteins might be of pathogenic relevance for human disease.

Key words: M-band, Limb-girdle muscular dystrophy, Myomesin, Obscurin, Titin

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