9m5y
From Proteopedia
the crystal structure of the Ca2+/CaM-CASK-CaMK complex
Structural highlights
DiseaseCSKP_HUMAN Defects in CASK are the cause of mental retardation and microcephaly with pontine and cerebellar hypoplasia (MICPCH) [MIM:300749. A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptative behavior and manifested during the developmental period. Patients with mental retardation X-linked CASK-related can manifest a severe phenotype consisting of severe intellectual deficit, congenital or postnatal microcephaly, disproportionate brainstem and cerebellar hypoplasia. A milder phenotype consists of mental retardation alone or associated with nystagmus.[1] Defects in CASK are the cause of FG syndrome type 4 (FGS4) [MIM:300422. FG syndrome (FGS) is an X-linked disorder characterized by mental retardation, relative macrocephaly, hypotonia and constipation.[2] FunctionCSKP_HUMAN 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. Publication Abstract from PubMedAs a member of the Ca(2+)/CaM-dependent protein kinase family, CASK contains an N-terminal CaMK domain that is regulated by Ca(2+)-bound CaM, while the underlying mechanism remains to be elucidated. Here, we determine the crystal structures of CASK-CaMK in different states: apo CASK-CaMK, CASK-CaMK in complex with CaM (the CaM-CASK complex) and CASK-CaMK in complex with CaM and Mint1 (the CaM-CASK-Mint1 complex). CASK-CaMK exhibits an inhibitory conformation with the alphaR2 helix of the autoregulatory domain (ARD) inserting into its nucleotide-binding pocket. Contrary to conventional CaM-mediated binding paradigms, in the CaM-CASK complex, only the C-terminal lobe of CaM (C-CaM) engages with the ARD of CASK-CaMK. This C-CaM binding induces the formation of an extended ARD alpha-helix that reshapes the nucleotide-binding pocket of CASK-CaMK to enhance its nucleotide-binding capacity. Correspondingly, in the CaM-CASK-Mint1 complex, similar C-CaM binding to CASK-CaMK leads to a slight opening of the CASK-Mint1 complex, and only the Mint1-CID (CASK-interaction domain) core is resolved association with CASK-CaMK. Taken together, CaM likely regulates CASK-CaMK through a C-CaM-dependent mechanism to tune its nucleotide-binding and target-recognition capacities. Structural basis for the Ca(2+)/CaM-mediated regulation of CASK-CaMK.,Li W, Wang Y, Feng W Int J Biol Macromol. 2025 Oct 26;332(Pt 1):148495. doi: , 10.1016/j.ijbiomac.2025.148495. PMID:41151710[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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