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Biophys J, June 2001, p. 2590-2596, Vol. 80, No. 6

Mutations in Calpain 3 Associated with Limb Girdle Muscular Dystrophy: Analysis by Molecular Modeling and by Mutation in m-Calpain

Zongchao Jia,* Vitali Petrounevitch,* Andrew Wong,* Tudor Moldoveanu,* Peter L. Davies,* John S. Elce,* and Jacques S. Beckmanndagger

 *Department of Biochemistry, Queen's University and The Protein Engineering Network of Centres of Excellence, Kingston, Ontario K7L 3N6, Canada; and  dagger Department of Molecular Genetics, Weizmann Institute of Science, 76100 Rehovot, Israel

Limb-girdle muscular dystrophy type 2A (LGMD2A) is an autosomal recessive disorder characterized by selective atrophy of the proximal limb muscles. Its occurrence is correlated, in a large number of patients, with defects in the human CAPN3 gene, a gene that encodes the skeletal muscle-specific member of the calpain family, calpain 3 (or p94). Because calpain 3 is difficult to study due to its rapid autolysis, we have developed a molecular model of calpain 3 based on the recently reported crystal structures of m-calpain and on the high-sequence homology between p94 and m-calpain (47% sequence identity). On the basis of this model, it was possible to explain many LGMD2A point mutations in terms of calpain 3 inactivation, supporting the idea that loss of calpain 3 activity is responsible for the disease. The majority of the LGMD2A mutations appear to affect domain/domain interaction, which may be critical in the assembly and the activation of the multi-domain calpain 3. In particular, we suggest that the flexibility of protease domain I in calpain 3 may play a critical role in the functionality of calpain 3. In support of the model, some clinically observed calpain 3 mutations were generated and analyzed in recombinant m-calpain. Mutations of residues forming intramolecular domain contacts caused the expected loss of activity, but mutations of some surface residues had no effect on activity, implying that these residues in calpain 3 may interact in vivo with other target molecules. These results contribute to an understanding of structure-function relationships and of pathogenesis in calpain 3.

Biophys J, June 2001, p. 2590-2596, Vol. 80, No. 6
© 2001 by the Biophysical Society   0006-3495/01/06/2590/07  $2.00


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