Human Molecular Genetics Advance Access published online on August 1, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn223
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NOVEL ROLE FOR CALPAIN-3 IN THE TRIAD-ASSOCIATED PROTEIN COMPLEX REGULATING CALCIUM RELEASE IN SKELETAL MUSCLE
1 Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA 2 Department of Molecular and Cellular Biology, University of Arizona, Tucson, Arizona 85724, USA
Corresponding author: Melissa J. Spencer, Ph.D., 635 Charles Young Dr, NRB, Rm. 401, Los Angeles, CA 90095 Tel.: 310-794-5225 Fax: 310-206-1998 E-mail: mspencer{at}mednet.usla.edu
Received June 17, 2008; Revised July 30, 2008; Accepted July 30, 2008
Calpain 3 is a non-lysosomal cysteine protease that is necessary for normal muscle function, as mutations in calpain 3 result in an autosomal recessive form of limb girdle muscular dystrophy type 2A (LGMD2A). To elucidate the biological roles of calpain 3 in skeletal muscle, we performed a search for potential substrates and interacting partners. By yeast-two-hybrid analysis we identified the glycolytic enzyme aldolase A as a binding partner for calpain 3. In co-expression studies calpain 3 degraded aldolase A; however, no accumulation of aldolase A was observed in total extracts from calpain 3 deficient muscles suggesting that aldolase A is not an in vivo substrate of calpain 3. Instead, we found calpain 3 to be necessary for recruitment of aldolase A to one specific location, namely the triads, which are structural components of muscle responsible for calcium transport and excitation-contraction coupling. Both aldolase and calpain 3 are present in the triad-enriched fraction and are able to interact with ryanodine receptors that form major calcium release channels. Levels of triad-associated aldolase A and ryanodine receptors were decreased in calpain 3 deficient muscles compared to wild type. Consistent with these observations we found calcium release to be significantly reduced in fibers from calpain 3 deficient muscles. Together, these data suggest that calpain 3 is necessary for the structural integrity of the triad-associated protein complex and that impairment of calcium transport is a phenotypic feature of calpain 3-deficient muscle.
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