ALTERNATIVE SPLICING OF AGRIN ALTERS ITS BINDING TO HEPARIN, DYSTROGLYCAN, AND THE PUTATIVE AGRIN RECEPTOR

Agrin is a heparan sulfate proteoglycan that induces aggregation of ac etylcholine receptors (AChRs) at the neuromuscular synapse. This aggre gating activity is modulated by alternative splicing. Here, we compare d binding of agrin isoforms to heparin, alpha-dystroglycan, and cultur ed myotubes. We find that the alternatively spliced 4 amino acid inser t (KSRK) is required for heparin binding. The binding affinity of agri n isoforms to alpha-dystroglycan correlates neither with binding to he parin nor with their AChR-aggregating activities. Moreover, the minima l fragment sufficient to induce AChR aggregation does not bind to alph a-dystroglycan. Nevertheless, this fragment still binds to cultured mu scle cells. Its binding is competed only by agrin isoforms that are ac tive in AChR aggregation, and therefore this binding site is likely to represent the receptor that initiates AChR clustering.