Abstract

CASK, an adaptor protein of the plasma membrane, is composed of an N-terminal calcium/calmodulin-dependent protein (CaM) kinase domain, central PSD-95, Dlg, and ZO-1/2 domain (PDZ) and Src homology 3 (SH3) domains, and a C-terminal guanylate kinase sequence. The CaM kinase domain of CASK binds to Mint 1, and the region between the CaM kinase and PDZ domains interacts with Velis, resulting in a tight tripartite complex. CASK, Velis, and Mint 1 are evolutionarily conserved in Caenorhabditis elegans, in which homologous genes (called lin-2, lin-7, and lin-10) are required for vulva development. We now demonstrate that the N-terminal CaM kinase domain of CASK binds to a novel brain-specific adaptor protein called Caskin 1. Caskin 1 and a closely related isoform, Caskin 2, are multidomain proteins containing six N-terminal ankyrin repeats, a single SH3 domain, and two sterile alpha motif domains followed by a long proline-rich sequence and a short conserved C-terminal domain. Unlike CASK and Mint 1, no Caskin homolog was detected in C. elegans. Immunoprecipitations showed that Caskin 1, like Mint 1, is stably bound to CASK in the brain. Affinity chromatography experiments demonstrated that Caskin 1 coassembles with CASK on the immobilized cytoplasmic tail of neurexin 1, suggesting that CASK and Caskin 1 coat the cytoplasmic tails of neurexins and other cell-surface proteins. Detailed mapping studies revealed that Caskin 1 and Mint 1 bind to the same site on the N-terminal CaM kinase domain of CASK and compete with each other for CASK binding. Our data suggest that in the vertebrate brain, CASK and Velis form alternative tripartite complexes with either Mint 1 or Caskin 1 that may couple CASK to distinct downstream effectors.

Keywords

CASKPDZ domainAnkyrin repeatGuanylate kinaseNeurexinBiologyC2 domainProtein kinase domainCell biologySH3 domainBinding siteC-terminusKinaseBiochemistryGeneticsMembrane proteinGeneProto-oncogene tyrosine-protein kinase SrcAmino acidReceptor

MeSH Terms

Adaptor ProteinsSignal TransducingAnimalsBinding SitesBindingCompetitiveCalcium-Calmodulin-Dependent Protein KinasesCarrier ProteinsCloningMolecularGuanylate KinasesHumansImmunohistochemistryMacromolecular SubstancesMembrane ProteinsMiceMolecular Sequence DataNerve Tissue ProteinsNucleoside-Phosphate KinaseOrgan SpecificityPrecipitin TestsProtein BindingProtein IsoformsProtein StructureTertiaryRNARatsRecombinant Fusion ProteinsSequence HomologyAmino Acid

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Publication Info

Year
2002
Type
article
Volume
22
Issue
11
Pages
4264-4273
Citations
133
Access
Closed

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Cite This

Katsuhiko Tabuchi, Thomas Biederer, Stefan Butz et al. (2002). CASK Participates in Alternative Tripartite Complexes in which Mint 1 Competes for Binding with Caskin 1, a Novel CASK-Binding Protein. Journal of Neuroscience , 22 (11) , 4264-4273. https://doi.org/10.1523/jneurosci.22-11-04264.2002

Identifiers

DOI
10.1523/jneurosci.22-11-04264.2002
PMID
12040031
PMCID
PMC6758797

Data Quality

Data completeness: 86%