Functional defects of a muscle-specific calpain, p94, caused by mutations associated with limb-girdle muscular dystrophy type 2A.

Abstract

p94 (calpain3), a muscle-specific member of the calpain family, has been shown to be responsible for limb-girdle muscular dystrophy type 2A (LGMD2A), a form of autosomal recessive and progressive neuromuscular disorder. To elucidate the molecular mechanism of LGMD2A, we constructed nine p94 missense point mutants found in LGMD2A and analyzed their p94 unique properties. All mutants completely or almost completely lose the proteolytic activity against a potential substrate, fodrin. However, some of the mutants still possess autolytic activity and/or connectin/titin binding ability, indicating these properties are not necessary for the LGMD2A phenotypes. These results provide strong evidence that LGMD2A results from the loss of proteolysis of substrates by p94, suggesting a novel molecular mechanism leading to muscular dystrophies.

• Authors: Y Ono, H Shimada, H Sorimachi, I Richard, T C Saido, J S Beckmann, S Ishiura, K Suzuki
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 273 Issue 27 Pg. 17073-8 (Jul 03 1998) ISSN: 0021-9258 [Print] United States
• PMID: 9642272 (Publication Type: Journal Article)

Chemical References

• Carrier Proteins
• Connectin
• Microfilament Proteins
• Muscle Proteins
• TTN protein, human
• fodrin
• Protein Kinases
• Calpain
• calpain p94

Topics

• Animals
• COS Cells
• Calpain (genetics, metabolism, physiology)
• Carrier Proteins (metabolism)
• Connectin
• Humans
• Hydrolysis
• Microfilament Proteins (metabolism)
• Muscle Proteins (metabolism)
• Muscular Dystrophies (genetics)
• Mutagenesis, Site-Directed
• Point Mutation
• Protein Kinases (metabolism)