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Human Molecular Genetics, 2000, Vol. 9, No. 7 1033-1040
© 2000 Oxford University Press

Biochemical evidence for association of dystrobrevin with the sarcoglycan–sarcospan complex as a basis for understanding sarcoglycanopathy

Mikiharu Yoshida1,+, Hiroshi Hama1, Michiko Ishikawa-Sakurai1, Michihiro Imamura1, Yuji Mizuno1, Kenji Araishi1, Eriko Wakabayashi-Takai1, Satoru Noguchi1,2, Toshikuni Sasaoka1 and Eijiro Ozawa1

1Department of Cell Biology, National Institute of Neuroscience, NCNP, 4-1-1 Ogawahigashi-chou, Kodaira, Tokyo 187-8502, Japan and 2Inheritance and Variation Group, PREST, Japan Science and Technology Corporation, Kawaguchi, Saitama 332-0012, Japan

The sarcoglycan complex is composed of four membrane-spanning dystrophin-associated proteins (DAPs) and is essential for skeletal muscle survival, since the absence or markedly reduced expression of this complex due to mutation of any one of the sarcoglycan genes causes a group of muscular dystrophies, collectively termed sarcoglycanopathy. Although one of the putative functions of the sarcoglycan complex is its participation in signaling processes, detailed studies have been scarce. Very recently, it was shown that gene knockout mice for a DAP, {alpha}-dystrobrevin, exhibit a dystrophic phenotype, possibly due to defects in muscle cell signaling. To clarify the putative function of the sarcoglycan complex, it is essential to determine whether or not there is a link between it and the intracellular signaling molecules. To elucidate this, we developed new methods for preparing various DAP complexes containing the sarcoglycan complex from the purified dystrophin–DAP complex. It was suggested from one of the complexes prepared that the sarco­glycan–sarcospan complex (the sarcoglycan complex associated with sarcospan) is associated with syntrophin and/or dystrobrevin. Further analysis of this complex revealed that the N-terminal half of dystrobrevin participates in this association. It is thus considered that the sarcoglycan–sarcospan complex is linked to the signaling protein neuronal nitric oxide synthase via {alpha}-syntrophin associated with dystrobrevin.

+ To whom correspondence should be addressed. Tel: +81 42 346 1720; Fax: +81 42 346 1750; Email: yoshida@ncnp.go.jp


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