6lnm
Crystal structure of CASK-CaMK in complex with Mint1-CID
Structural highlights
FunctionCSKP_RAT Multidomain scaffolding protein with a role in synaptic transmembrane protein anchoring and ion channel trafficking. Contributes to neural development and regulation of gene expression via interaction with the transcription factor TRB1. Binds to cell-surface proteins, including amyloid precursor protein, neurexins, and syndecans. May mediate a link between the extracellular matrix and the actin cytoskeleton via its interaction with syndecan and with the actin/spectrin-binding protein 4.1.[1] Publication Abstract from PubMedCASK forms an evolutionarily conserved tripartite complex with Mint1 and Veli critical for neuronal synaptic transmission and cell polarity. The CASK CaM kinase (CaMK) domain, in addition to interacting with Mint1, can also bind to many different target proteins, although the mechanism governing CASK-CaMK/target interaction selectivity is unclear. Here, we demonstrate that an extended sequence in the N-terminal unstructured region of Mint1 binds to CASK-CaMK with a dissociation constant of approximately 7.5 nM. The high-resolution crystal structure of CASK-CaMK in complex with this Mint1 fragment reveals that the C-lobe of CASK-CaMK binds to a short sequence common to known CaMK targets and the N-lobe of CaMK engages an alpha helix that is unique to Mint1. Biochemical experiments together with structural analysis reveal that the CASK and Mint1 interaction is not regulated by Ca(2+)/CaM. The CASK/Mint1 complex structure provides mechanistic explanations for several CASK mutations identified in patients with brain disorders and cancers. Structural Basis for the High-Affinity Interaction between CASK and Mint1.,Wu X, Cai Q, Chen Y, Zhu S, Mi J, Wang J, Zhang M Structure. 2020 Jun 2;28(6):664-673.e3. doi: 10.1016/j.str.2020.04.001. Epub 2020, Apr 28. PMID:32348748[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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