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

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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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