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

Abstract

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.

• Authors: Atsushi Fukuzawa, Stephan Lange, Mark Holt, Anna Vihola, Virginie Carmignac, Ana Ferreiro, Bjarne Udd, Mathias Gautel
• Journal: Journal of cell science (J Cell Sci) Vol. 121 Issue 11 Pg. 1841-51 (Jun 01 2008) ISSN: 0021-9533 [Print] England
• PMID: 18477606 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Connectin
• Cytoskeletal Proteins
• Guanine Nucleotide Exchange Factors
• Muscle Proteins
• OBSL1 protein, rat
• Obscn protein, rat
• RNA, Small Interfering
• TCAP protein, human
• Ttn protein, rat

Topics

• Animals
• Animals, Newborn
• Binding Sites (genetics)
• Cells, Cultured
• Connectin
• Cytoskeletal Proteins (chemistry, metabolism)
• Down-Regulation (physiology)
• Guanine Nucleotide Exchange Factors (chemistry, metabolism)
• Muscle Proteins (chemistry, genetics, metabolism)
• Muscle, Skeletal (metabolism, ultrastructure)
• Muscular Diseases (genetics, metabolism, physiopathology)
• Mutation (genetics)
• Myocytes, Cardiac (metabolism, ultrastructure)
• Protein Binding (genetics)
• Protein Structure, Tertiary (physiology)
• RNA, Small Interfering
• Rats
• Sarcomeres (metabolism, ultrastructure)