The N-terminal PDZ-containing region of postsynaptic density-95 mediates association with caveolar-like lipid domains

Postsynaptic density-95 (PSD-95) is a palmitoylated peripheral membrane PDZ protein that organizes signaling molecules at synaptic sites. Here we find the amino terminal region of PSD-95, containing the three PDZ domains is n ecessary and sufficient to localize PSD-95 to caveolar-like domains. In tra nsfected COS cells, a subpopulation of PSD-95 is buoyant in sucrose gradien ts, and co-migrates with caveolin, a marker for caveolar domains. Sucrose g radient separation of brain extracts showed that some neuronal PSD-95 prote in is present in buoyant fractions as well. Analysis of truncated forms of the PSD-95 indicated that the N-terminal PDZ-containing region localizes to caveolae, but the C-terminal region, containing the SH3 and the guanylate kinase domains does not. The mechanism by which the N-terminal region targe ts PSD-95 to buoyant lipid domains remains unknown. PSD-95 does not interac t with caveolin and palmitoylation of PSD-95 is not required for caveolar f ractionation. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved.