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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Spencer, Melissa J. Ermolova, Natalia Kramerova, Irina |
| Description | Author Affiliation: Ermolova N ( From the Department of Neurology, Geffen School of Medicine, and Center for Duchenne Muscular Dystrophy, UCLA, Los Angeles, CA 90095.); Kramerova I ( From the Department of Neurology, Geffen School of Medicine, and Center for Duchenne Muscular Dystrophy, UCLA, Los Angeles, CA 90095.); Spencer MJ ( From the Department of Neurology, Geffen School of Medicine, and Center for Duchenne Muscular Dystrophy, UCLA, Los Angeles, CA 90095 mspencer@mednet.ucla.edu.) |
| Abstract | Calpains are broadly distributed, calcium-dependent enzymes that induce limited proteolysis in a wide range of substrates. Mutations in the gene encoding the muscle-specific family member calpain 3 (CAPN3) underlie limb-girdle muscular dystrophy 2A. We have shown previously that CAPN3 knockout muscles exhibit attenuated calcium release, reduced calmodulin kinase (CaMKII) signaling, and impaired muscle adaptation to exercise. However, neither the precise role of CAPN3 in these processes nor the mechanisms of CAPN3 activation in vivo have been fully elucidated. In this study, we identify calmodulin (CaM), a known transducer of the calcium signal, as the first positive regulator of CAPN3 autolytic activity. CaM was shown to bind CAPN3 at two sites located in the C2L domain. Biochemical studies using muscle extracts from transgenic mice overexpressing CAPN3 or its inactive mutant revealed that CaM binding enhanced CAPN3 autolytic activation. Furthermore, CaM facilitated CAPN3-mediated cleavage of its in vivo substrate titin in tissue extracts. Therefore, these studies reveal a novel interaction between CAPN3 and CaM and identify CaM as the first positive regulator of CAPN3 activity. |
| ISSN | 00219258 |
| e-ISSN | 1083351X |
| Journal | Journal of Biological Chemistry |
| Issue Number | 2 |
| Volume Number | 290 |
| Language | English |
| Publisher | American Society for Biochemistry and Molecular Biology (United States) |
| Publisher Date | 2015-01-09 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Calcium-Calmodulin-Dependent Protein Kinase Type 2 Genetics Calmodulin Calpain Muscle Proteins Muscular Dystrophies, Limb-Girdle Proteolysis Animals Calcium Signaling Metabolism Biosynthesis Mice Mice, Transgenic Muscle, Skeletal Pathology Mutation Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Biochemistry Molecular Biology |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cell Biology Biochemistry Molecular Biology |
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