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CRYSTAL STRUCTURE OF THE HUMAN CDKL2 KINASE DOMAIN WITH BOUND TCS 2312CRYSTAL STRUCTURE OF THE HUMAN CDKL2 KINASE DOMAIN WITH BOUND TCS 2312
Structural highlights
FunctionPublication Abstract from PubMedVarious kinases, including a cyclin-dependent kinase (CDK) family member, regulate the growth and functions of primary cilia, which perform essential roles in signaling and development. Neurological disorders linked to CDK-Like (CDKL) proteins suggest that these underexplored kinases may have similar functions. Here, we present the crystal structures of human CDKL1, CDKL2, CDKL3, and CDKL5, revealing their evolutionary divergence from CDK and mitogen-activated protein kinases (MAPKs), including an unusual ?J helix important for CDKL2 and CDKL3 activity. C. elegans CDKL-1, most closely related to CDKL1-4 and localized to neuronal cilia transition zones, modulates cilium length; this depends on its kinase activity and ?J helix-containing C terminus. Human CDKL5, linked to Rett syndrome, also localizes to cilia, and it impairs ciliogenesis when overexpressed. CDKL5 patient mutations modeled in CDKL-1 cause localization and/or cilium length defects. Together, our studies establish a disease model system suggesting cilium length defects as a pathomechanism for neurological disorders, including epilepsy. CDKL Family Kinases Have Evolved Distinct Structural Features and Ciliary Function.,Canning P, Park K, Goncalves J, Li C, Howard CJ, Sharpe TD, Holt LJ, Pelletier L, Bullock AN, Leroux MR Cell Rep. 2018 Jan 23;22(4):885-894. doi: 10.1016/j.celrep.2017.12.083. Epub 2018, Jan 28. PMID:29420175[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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