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© The Rockefeller University Press, 0021-9525/1997//669 $5.00
The Journal of Cell Biology, Volume 136, Number 3, , 1997 669-678

Article

GKAP, a Novel Synaptic Protein That Interacts with the Guanylate Kinase-like Domain of the PSD-95/SAP90 Family of Channel Clustering Molecules



Eunjoon Kim, Scott Naisbitt, Yi-Ping Hsueh, Anuradha Rao*, Adam Rothschild, Ann Marie Craig*, and Morgan Sheng

Howard Hughes Medical Institute and Department of Neurobiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114; and * Department of Cell and Structural Biology, University of Illinois, Urbana-Champaign, Illinois 61801

The molecular mechanisms underlying the organization of ion channels and signaling molecules at the synaptic junction are largely unknown. Recently, members of the PSD-95/SAP90 family of synaptic MAGUK (membrane-associated guanylate kinase) proteins have been shown to interact, via their NH2-terminal PDZ domains, with certain ion channels (NMDA receptors and K+ channels), thereby promoting the clustering of these proteins. Although the function of the NH2-terminal PDZ domains is relatively well characterized, the function of the Src homology 3 (SH3) domain 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 novel synaptic protein, termed GKAP for guanylate kinase-associated protein, that binds directly to the GK domain of the four known members of the mammalian PSD-95 family. GKAP shows a unique domain structure and appears to be a major constituent of the postsynaptic density. GKAP colocalizes and coimmunoprecipitates with PSD-95 in vivo, and coclusters with PSD-95 and K+ channels/ NMDA receptors in heterologous cells. Given their apparent lack of guanylate kinase enzymatic activity, the fact 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).

Abbreviations used in this paper: GKAP, guanylate kinase-associated protein; PSD-95, postsynaptic density-95; SAP90, synapse-associated protein 90; NMDA, N-methyl-d-aspartate; ZO-1, zona occludens-1.

Please address all correspondence to M. Sheng, HHMI, (Wellman 423), Massachusetts General Hospital, 50 Blossom Street, Boston, MA 02114. Tel.: (617) 724-2800. Fax: (617) 724-2805. E-Mail: sheng{at}helix.mgh.harvard.edu


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