Disruption of obscurin-M-band integration via titin mutations provides a molecular basis for the pathogenesis of hereditary myopathies like LGMD2J and Salih myopathy.
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.
Fukuzawa et al. (Wed,) studied this question.