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JCS ePress
online publication date 13 May 2008
doi: 10.1242/jcs.028019
Research Article
Interactions with titin and myomesin target obscurin and obscurin-like 1 to the M-band - implications for hereditary myopathies
Atsushi Fukuzawa,
Stephan Lange,
Mark Holt,
Anna Vihola,
Virginie Carmignac,
Ana Ferreiro,
Bjarne Udd,
and
Mathias Gautel*
* Author for correspondence (e-mail: mathias.gautel{at}kcl.ac.uk)
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.
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