Membrane targeting and stabilization of sarcospan is mediated by the sarcoglycan subcomplex

The dystrophin-glycoprotein complex (DGC) is a multisubunit complex that sp ans the muscle plasma membrane and forms a link between the F-actin cytoske leton and the extracellular matrix. The proteins of the DGC ape structurall y organized into distinct subcomplexes, and genetic mutations in many indiv idual components are manifested as muscular dystrophy. We recently identifi ed a unique tetraspan-like dystrophin-associated protein, which we have nam ed sarcospan (SPN) for its multiple sarcolemma spanning domains (Crosbie, R .H,, J, Heighway, D.P. Venzke, J.C. Lee, and K.P. Campbell. 1997. J. Biol. Chem. 272:31221-31224). To probe molecular associations of SPN within the D GC, we investigated SPN expression in normal muscle as a baseline for compa rison to SPN's expression in animal models of muscular dystrophy. We show t hat, in addition to its sarcolemma localization, SPN is enriched at the myo tendinous junction (MTJ) and neuromuscular junction (NMJ), where it is a co mponent of both the dystrophin- and utrophin-glycoprotein complexes. We dem onstrate that SPN is preferentially associated with the sarcoglycan (SG) su bcomplex, and this interaction is critical for stable localization of SPN t o the sarcolemma, NMJ, and MTJ. Our experiments indicate that assembly of t he SG subcomplex is a prerequisite for targeting SPN to the sarcolemma. In addition, the SG-SPN subcomplex functions to stabilize alpha-dystroglycan t o the muscle plasma membrane. Taken together, our data provide important in formation about assembly and function of the SG-SPN subcomplex.