DISULFIDE-LINKED HEAD-TO-HEAD MULTIMERIZATION IN THE MECHANISM OF ION-CHANNEL CLUSTERING BY PSD-95

The PSD-95/SAP90 family of PDZ-containing proteins is directly involve d in the clustering of specific ion channels at synapses. We report th at channel clustering depends on a conserved N-terminal domain of PSD- 95 that mediates multimerization and disulfide linkage of PSD-95 proto mers. This N-terminal multimerization domain confers channel clusterin g activity on a single PDZ domain. Thus, channel clustering depends on aggregation of PDZ domains achieved by head-to-head multimerization o f PSD-95, rather than by concatenation of PDZ domains in PSD-95 monome rs. This mechanism predicts that PSD-95 can organize heterogeneous mem brane protein clusters via differential binding specificities of its t hree PDZ domains. PSD-95 and its relative chapsyn-110 exist as disulfi de-linked complexes in rat brain, consistent with head-to-head multime rization of these proteins in vivo.