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

The sarcoglycan complex is composed of four membrane-spanning dystrophin-as sociated proteins (DAPs) and is essential for skeletal muscle survival, sin ce the absence or markedly reduced expression of this complex due to mutati on of any one of the sarcoglycan genes causes a group of muscular dystrophi es, collectively termed sarcoglycanopathy, Although one of the putative fun ctions of the sarcoglycan complex is its participation in signaling process es, detailed studies have been scarce. Very recently, it was shown that gen e knockout mice for a DAP, alpha-dystrobrevin, exhibit a dystrophic phenoty pe, possibly due to defects in muscle cell signaling, To clarify the putati ve function of the sarcoglycan complex, it is essential to determine whethe r or not there is a link between it and the intracellular signaling molecul es, To elucidate this, we developed new methods for preparing various DAP c omplexes containing the sarcoglycan complex from the purified dystrophin-DA P complex, It was suggested from one of the complexes prepared that the sar coglycan-sarcospan complex (the sarcoglycan complex associated with sarcosp an) 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 v ia alpha-syntrophin associated with dystrobrevin.