Abstract
CASK, a MAGUK family protein, is an essential protein present in the presynaptic compartment. CASK's cellular role is unknown, but it interacts with multiple proteins important for synapse formation and function, including neurexin, liprin-α, and Mint1. CASK phosphorylates neurexin in a divalent ion-sensitive manner, although the functional relevance of this activity is unclear. Here we find that liprin-α and Mint1 compete for direct binding to CASK, but neurexin1β eliminates this competition, and all four proteins form a complex. We describe a novel mode of interaction between liprin-α and CASK when CASK is bound to neurexin1β. We show that CASK phosphorylates neurexin, modulating the interaction of liprin-α with the CASK-neurexin1β-Mint1 complex. Thus, CASK creates a regulatory and structural link between the presynaptic adhesion molecule neurexin and active zone organizer, liprin-α. In neuronal culture, CASK appears to regulate the stability of neurexin by linking it with this multi-protein presynaptic active zone complex.
Keywords:
Active zone; Mint1; Neuron; Protein complex; Protein phosphorylation; Protein turnover; Protein–protein interaction; Synapse.
MeSH terms
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Adaptor Proteins, Signal Transducing / chemistry
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Adaptor Proteins, Signal Transducing / metabolism
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Amino Acid Sequence
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Animals
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Calcium-Binding Proteins
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Cell Membrane / metabolism
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Cells, Cultured
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Female
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Guanylate Kinases / chemistry
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Guanylate Kinases / genetics
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Guanylate Kinases / metabolism*
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HEK293 Cells
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Humans
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Male
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Mice
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Mice, Inbred C57BL
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Nerve Tissue Proteins / chemistry
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Nerve Tissue Proteins / metabolism
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Neural Cell Adhesion Molecules / chemistry
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Neural Cell Adhesion Molecules / metabolism*
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Neurons / cytology
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Neurons / metabolism*
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Protein Binding
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Protein Interaction Domains and Motifs
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Protein Isoforms / genetics
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Protein Isoforms / metabolism
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Protein Structure, Tertiary
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Proteins / chemistry
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Proteins / genetics
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Proteins / metabolism*
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Rats
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Rats, Long-Evans
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Rats, Sprague-Dawley
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Recombinant Proteins / biosynthesis
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Recombinant Proteins / chemistry
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Recombinant Proteins / isolation & purification
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Sequence Alignment
Substances
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Adaptor Proteins, Signal Transducing
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Apba1 protein, mouse
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Calcium-Binding Proteins
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Nerve Tissue Proteins
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Neural Cell Adhesion Molecules
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Nrxn1 protein, mouse
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Ppfia1 protein, mouse
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Protein Isoforms
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Proteins
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Recombinant Proteins
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CASK kinases
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Guanylate Kinases