Interactions with M-band titin and calpain 3 link myospryn (CMYA5) to tibial and limb-girdle muscular dystrophies.

Abstract

Mutations in the C terminus of titin, situated at the M-band of the striated muscle sarcomere, cause tibial muscular dystrophy (TMD) and limb-girdle muscular dystrophy (LGMD) type 2J. Mutations in the protease calpain 3 (CAPN3), in turn, lead to LGMD2A, and secondary CAPN3 deficiency in LGMD2J suggests that the pathomechanisms of the diseases are linked. Yeast two-hybrid screens carried out to elucidate the molecular pathways of TMD/LGMD2J and LGMD2A resulted in the identification of myospryn (CMYA5, cardiomyopathy-associated 5) as a binding partner for both M-band titin and CAPN3. Additional yeast two-hybrid and coimmunoprecipitation studies confirmed both interactions. The interaction of myospryn and M-band titin was supported by localization of endogenous and transfected myospryn at the M-band level. Coexpression studies showed that myospryn is a proteolytic substrate for CAPN3 and suggested that myospryn may protect CAPN3 from autolysis. Myospryn is a muscle-specific protein of the tripartite motif superfamily, reported to function in vesicular trafficking and protein kinase A signaling and implicated in the pathogenesis of Duchenne muscular dystrophy. The novel interactions indicate a role for myospryn in the sarcomeric M-band and may be relevant for the molecular pathomechanisms of TMD/LGMD2J and LGMD2A.

• Authors: Jaakko Sarparanta, Gaëlle Blandin, Karine Charton, Anna Vihola, Sylvie Marchand, Astrid Milic, Peter Hackman, Elisabeth Ehler, Isabelle Richard, Bjarne Udd
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 285 Issue 39 Pg. 30304-15 (Sep 24 2010) ISSN: 1083-351X [Electronic] United States
• PMID: 20634290 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CMYA5 protein, human
• Connectin
• Muscle Proteins
• TTN protein, human
• Protein Kinases
• Cyclic AMP-Dependent Protein Kinases
• CAPN3 protein, human
• Calpain

Topics

• Amino Acid Motifs
• Biological Transport
• Calpain (genetics, metabolism)
• Connectin
• Cyclic AMP-Dependent Protein Kinases (genetics, metabolism)
• Humans
• Muscle Proteins (genetics, metabolism)
• Muscular Dystrophies, Limb-Girdle (genetics, metabolism)
• Mutation
• Protein Binding
• Protein Kinases (genetics, metabolism)
• Sarcomeres (genetics, metabolism)
• Signal Transduction
• Two-Hybrid System Techniques