GKAP, a novel synaptic protein that interacts with the guanylate kinase-like domain of the PSD-95/SAP90 family of channel clustering molecules

J Cell Biol. 1997 Feb 10;136(3):669-78. doi: 10.1083/jcb.136.3.669.

Abstract

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).

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Binding Sites
  • COS Cells
  • Carrier Proteins / genetics*
  • Carrier Proteins / metabolism
  • Disks Large Homolog 4 Protein
  • Guanylate Kinases
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Ion Channels
  • Membrane Proteins
  • Molecular Sequence Data
  • Nerve Tissue Proteins / metabolism*
  • Nucleoside-Phosphate Kinase / metabolism
  • Proteins / genetics
  • Proteins / metabolism*
  • Rats
  • SAP90-PSD95 Associated Proteins
  • Synapses / metabolism

Substances

  • Carrier Proteins
  • DLG4 protein, human
  • DLGAP1 protein, human
  • Disks Large Homolog 4 Protein
  • Dlg4 protein, rat
  • Intracellular Signaling Peptides and Proteins
  • Ion Channels
  • Membrane Proteins
  • Mpp2 protein, rat
  • Nerve Tissue Proteins
  • Proteins
  • SAP90-PSD95 Associated Proteins
  • postsynaptic density proteins
  • Nucleoside-Phosphate Kinase
  • Guanylate Kinases

Associated data

  • GENBANK/U67987
  • GENBANK/U67988