Mutations in calpain 3 associated with limb girdle muscular dystrophy: analysis by molecular modeling and by mutation in m-calpain

Détails

ID Serval
serval:BIB_09BD24893CEF
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Mutations in calpain 3 associated with limb girdle muscular dystrophy: analysis by molecular modeling and by mutation in m-calpain
Périodique
Biophysical Journal
Auteur(s)
Jia  Z., Petrounevitch  V., Wong  A., Moldoveanu  T., Davies  P. L., Elce  J. S., Beckmann  J. S.
ISSN
0006-3495 (Print)
Statut éditorial
Publié
Date de publication
06/2001
Volume
80
Numéro
6
Pages
2590-6
Notes
Journal Article
Research Support, Non-U.S. Gov't --- Old month value: Jun
Résumé
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.
Mots-clé
Amino Acid Sequence Animals Calpain/*chemistry/*genetics/metabolism Humans *Isoenzymes Models, Molecular Molecular Sequence Data *Muscle Proteins Muscular Dystrophies/*enzymology/*genetics Mutagenesis, Site-Directed Protein Structure, Tertiary Rats Sequence Alignment Structure-Activity Relationship
Pubmed
Web of science
Open Access
Oui
Création de la notice
25/01/2008 16:17
Dernière modification de la notice
20/08/2019 12:31
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