CASK: a novel dlg/PSD95 homolog with an N-terminal calmodulin-dependent protein kinase domain identified by interaction with neurexins
Open accessAbstract
Neurexins are neuronal cell surface proteins with hundreds of isoforms. In yeast two-hybrid screens for intracellular molecules interacting with different neurexins, we identified a single interacting protein called CASK. CASK is composed of an N-terminal Ca2+, calmodulin- dependent protein kinase sequence and a C-terminal region that is similar to the intercellular junction proteins dlg-A, PSD95/SAP90, SAP97, Z01, and Z02 and that contains DHR-, SH3-, and guanylate kinase domains. CASK is enriched in brain in synaptic plasma membranes but is also detectable at low levels in all tissues tested. The cytoplasmic domains of all three neurexins bind CASK in a salt-labile interaction. In neurexin I, this interaction is dependent on the C-terminal three residues. Thus, CASK is a membrane-associated protein that combines domains found in Ca2+ - activated protein kinases and in proteins specific for intercellular junctions, suggesting that it may be a signaling molecule operating at the plasma membrane, possibly in conjunction with neurexins.
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The CASK PDZ-domain tightly binds to the C terminus of neurexins, constituting the first example of a "type II" PDZ-domain interaction.
“CASK was discovered because its PDZ-domain—a component of the MAGUK domains—tightly binds to the C terminus of neurexins, thereby constituting the first example of a “type II” PDZ-domain interaction (Hata et al., 1996).”
From The Presynaptic Active Zone (2012) · cites this paper as Hata et al., 1996
The Abstract (page unavailable) reports that CASK was identified through its interaction with neurexins and that binding to neurexin I depends on its C-terminal three residues. The Properties and tissue distribution section (page unavailable) says the interaction is salt-labile and suggests it is weak; it does not establish binding by the PDZ domain specifically or call this the first type II PDZ-domain interaction. (LLM, conf=0.88)
Experimental — accuracy not yet measuredCASK is composed of an N-terminal CaM kinase-like domain that constitutes a catalytically active, unusual protein kinase, and a C-terminal set of domains characteristic of MAGUKs.
“CASK is composed of an N-terminal CaM kinase-like domain that constitutes a catalytically active, unusual protein kinase (Mukherjee et al., 2008), and a C-terminal set of domains characteristic of MAGUKs (for membrane-associated guanylate kinases; Hata et al., 1996).”
From The Presynaptic Active Zone (2012) · cites this paper as Hata et al., 1996
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- Authors
- Hata, Y., Butz, S., & Sudhof, T.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 1996-04-15
- Volume
- 16
- Issue
- 8
- Pages
- 2488-2494
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6578772
- OpenAlex
- W1919311176
- Cited by
- 553
- References
- 1
- Citations by year
- 2026: 13 · 2025: 7 · 2024: 6 · 2023: 19 · 2022: 21 · 2021: 19 · 2020: 15 · 2019: 13 · 2018: 11 · 2017: 13 · 2016: 15 · 2015: 15 · 2014: 20 · 2013: 17 · 2012: 15
- FWCI
- 10.56
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Mental Health (R01 MH52804, R01MH052804)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- CASK, neurexin, calcium/calmodulin-dependent protein kinase, PSD-95, synaptic plasma membrane, SH3 domain, guanylate kinase domain, protein-protein interaction, brain, signaling molecules
- MeSH terms
- Animals, Base Sequence, Brain, Cloning, Molecular, Molecular Sequence Data, Protein Kinases, Calcium-Calmodulin-Dependent Protein Kinases, Rats
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