Interactions with M-band titin and calpain 3 link myospryn (CMYA5) to tibial and limb-girdle muscular dystrophies.
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.
Sarparanta
Jaakko
J
Department of Medical Genetics, Folkhälsan Institute of Genetics, University of Helsinki, 00014 Helsinki, Finland. jaakko.sarparanta@helsinki.fi
Blandin
Gaëlle
G
Charton
Karine
K
Vihola
Anna
A
Marchand
Sylvie
S
Milic
Astrid
A
Hackman
Peter
P
Ehler
Elisabeth
E
Richard
Isabelle
I
Udd
Bjarne
B
D020816:Amino Acid Motifs; D001692:Biological Transport; D002154:Calpain / Q000235:genetics / Q000378:metabolism*; D064211:Connectin; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D049288:Muscular Dystrophies, Limb-Girdle / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D011485:Protein Binding; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D012518:Sarcomeres / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D020798:Two-Hybrid System Techniques
C430866:CMYA5 protein, human; D064211:Connectin; D009124:Muscle Proteins; C577285:TTN protein, human; D011494:Protein Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; C105884:CAPN3 protein, human; D002154:Calpain