GKAP, a Novel Synaptic Protein That Interacts with the Guanylate Kinase-like Domain of the PSD-95/SAP90 Family of Channel Clustering Molecules
Open accessAbstract
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).
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Shank family proteins bind SAPAP directly to form the PSD95/SAPAP/Shank complex.
“Shank family proteins (Shank1–3) directly bind SAPAP to form the PSD95/SAPAP/Shank complex14,15.”
From Shank3 mutant mice display autistic-like behaviours and striatal dysfunction (2011) · cites this paper as [14]
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- Authors
- Kim, E., Naisbitt, S., Hsueh, Y.-P., Rao, A., Rothschild, A., Craig, A. M., & Sheng, M.
- Affiliations
- Howard Hughes Medical Institute (US)
- Venue
- The Journal of Cell Biology
- Publisher
- Rockefeller University Press
- Published
- 1997-02-10
- Volume
- 136
- Issue
- 3
- Pages
- 669-678
- ISSN
- 0021-9525 (ISSN-L)
- 1540-8140
- PMC
- PMC2134290
- OpenAlex
- W2068240232
- Cited by
- 516
- References
- 33
- Citations by year
- 2026: 4 · 2025: 9 · 2024: 9 · 2023: 7 · 2022: 16 · 2021: 10 · 2020: 9 · 2019: 14 · 2018: 19 · 2017: 11 · 2016: 20 · 2015: 8 · 2014: 14 · 2013: 13 · 2012: 14
- FWCI
- 17.20
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- cc-by-nc-sa
- Locations
- The Journal of Cell Biology (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (NS33184, R01NS033184)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- GKAP, PSD-95, synaptic proteins, postsynaptic density, ion channel clustering, NMDA receptor, potassium channels, PDZ domain, SH3 domain, protein-protein interaction, MAGUK proteins, p55, ZO-1
- MeSH terms
- SAP90-PSD95 Associated Proteins, Disks Large Homolog 4 Protein, Amino Acid Sequence, Animals, Base Sequence, Binding Sites, Carrier Proteins, Humans, Ion Channels, Membrane Proteins, Molecular Sequence Data, Nerve Tissue Proteins, Nucleoside-Phosphate Kinase, Proteins, Synapses, COS Cells, Intracellular Signaling Peptides and Proteins, Rats, Guanylate Kinases
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