| Co-Investigator(Kenkyū-buntansha) |
BECKMANN Jacques Genethon Institute, Director, 部長(研究職)
KIMURA Sumiko Chiba University, Faculty of Science, Associate Professor, 理学部, 助教授 (50093232)
SORIMACHI Hiroyuki University of Tokyo, Graduate School of Agriculture and Life, Associate Professo, 大学院・農学生命科学研究科, 助教授 (10211327)
ISHIURA Shoichi University of Tokyo, Graduate School of Arts & Sciences Professor, 大学院・総合文化研究所, 教授 (10158743)
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| Research Abstract |
Calpain is a typical intracellular Ca-dependent protease and hydrolyzes various cellular proteins in a limited manner, changes their properties, and known as a biomodulator. p94 is a calpain homologue expressed specifically in skeletal muscle. p94 is unique in having various properties distinct from ordinary ubiquitous calpains, e.g. autolyzes very rapidly apparently in the absence of Ca2+, binds to connectin in skeletal muscle at least at two specific sites, contains a nuclear translocation signal, has three insertion sequences, hydrolyzes fodrin, calpastatin, HSP6O, etc.
Quite recently, p94 has been identified as a gene responsible for limb-girdle type 2A muscular dystrophy (LGMD2A). We selected 10 point mutants from various mutants found in LGMD2A patients and the point mutants were expressed in COS cells. Expressed p94 point mutants were examined for the unique properties listed above in order to identify which properties are directly correlated to LGMD2A.Binding to connectin and rapid autolysis showed no direct correlation to LGMD2A but a toss of proteolytic activity against fodrin, calpastatin, HSP6O resulted in LGMD2A Thus the next important issue is to identify a substrate(s) of p94 which directly or eventually activates degradation of muscle proteins and to clarify a mechanism for activation of muscle protein degradation. Studies are now in progress along this line.
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