title: The molecular basis of the Caskin1 and Mint1 interaction with CASK.
abstract: Calcium/calmodulin-dependent serine protein kinase (CASK) is a conserved multi-domain scaffolding protein involved in brain development, synapse formation, and establishment of cell polarity. To accomplish these diverse functions, CASK participates in numerous protein-protein interactions. In particular, CASK forms competing CASK/Mint1/Velis and CASK/Caskin1/Velis tripartite complexes that physically associate with the cytoplasmic tail of neurexin, a transmembrane protein enriched at presynaptic sites. This study shows that a short linear EEIWVLRK peptide motif from Caskin1 is necessary and sufficient for binding CASK. We also identified the conserved binding site for the peptide on the CASK calmodulin kinase domain. A related EPIWVMRQ peptide from Mint1 was also discovered to be sufficient for binding. Searching all human proteins for the Mint1/Caskin1 consensus peptide ExIWVxR revealed that T-cell lymphoma invasion and metastasis 1 (TIAM1) contains a conserved EEVIWVRRE peptide that was also found to be sufficient for CASK binding in vitro. TIAM1 is well known for its role in tumor metastasis, but it also possesses overlapping cellular and neurological functions with CASK, suggesting a previously unknown cooperation between the two proteins. This new peptide interaction motif also explains how Caskin1 and Mint1 form competing complexes and suggests a new role for the cellular hub protein CASK.
authors.affiliation: Department of Chemistry and Biochemistry, UCLA-DOE Institute of Genomics and Proteomics, Molecular Biology Institute, University of California, Los Angeles, Boyer Hall, 611 Charles E. Young Drive East, Los Angeles, CA 90095-1570, USA.
authors.forename: Ryan L
authors.initials: RL
authors.lastname: Stafford
authors.forename: Jason
authors.initials: J
authors.lastname: Ear
authors.forename: Mary Jane
authors.initials: MJ
authors.lastname: Knight
authors.forename: James U
authors.initials: JU
authors.lastname: Bowie
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D001665:Binding Sites / Q000235:genetics; D002850:Chromatography, Gel; D002942:Circular Dichroism; D051528:Guanylate Kinases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000235:genetics / Q000502:physiology; D017386:Sequence Homology, Amino Acid; D020349:Surface Plasmon Resonance
chemical_list: C079091:APBA1 protein, human; D048868:Adaptor Proteins, Signal Transducing; C473247:CASKIN1 protein, human; D009419:Nerve Tissue Proteins; C106868:CASK kinases; D051528:Guanylate Kinases