GKAP, A NOVEL SYNAPTIC PROTEIN THAT INTERACTS WITH THE GUANYLATE KINASE-LIKE DOMAIN OF THE PSD-95 SAP90 FAMILY OF CHANNEL CLUSTERING MOLECULES/

The molecular mechanisms underlying the organization of ion channels a nd signaling molecules at the synaptic junction are largely unknown. R ecently, members of the PSD-95/SAP90 family of synaptic MAGUK (membran e-associated guanylate kinase) proteins have been shown to interact, v ia their NH2-terminal PDZ domains, with certain ion channels (NMDA rec eptors and K+ channels), thereby promoting the clustering of these pro teins. Although the function of the NH2-terminal PDZ domains is relati vely well characterized, the function of the Src homology 3 (SH3) doma in and the guanylate kinase-like (GK) domain in the COOH-terminal half of PSD-95 has remained obscure. We now report the isolation of a nove l synaptic protein, termed GKAP for guanylate kinase-associated protei n, that binds directly to the GK domain of the four known members of t he mammalian PSD-95 family. GKAP shows a unique domain structure and a ppears to be a major constituent of the postsynaptic density. GKAP col ocalizes and coimmunoprecipitates with PSD-95 in vivo, and coclusters with PSD-95 and K+ channels/ NMDA receptors in heterologous cells. Giv en their apparent lack of guanylate kinase enzymatic activity, the fac t that the GK domain can act as a site for protein-protein interaction has implications for the function of diverse GK-containing proteins ( such as p55, ZO-1, and LIN-2/CASK).