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CDKL Family Kinases Have Evolved Distinct Structural Features and Ciliary Function

Canning, Peter and Park, Kwangjin and Gonçalves, João and Li, Chunmei and Howard, Conor J. and Sharpe, Timothy D. and Holt, Liam J. and Pelletier, Laurence and Bullock, Alex N. and Leroux, Michel R.. (2018) CDKL Family Kinases Have Evolved Distinct Structural Features and Ciliary Function. Cell Reports, 22 (4). pp. 885-894.

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Abstract

Various 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.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Services Biozentrum > Biophysics Facility (Sharpe)
UniBasel Contributors:Sharpe, Timothy
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Cell Press
e-ISSN:2211-1247
Note:Publication type according to Uni Basel Research Database: Journal article
Language:English
Identification Number:
Last Modified:02 May 2018 07:31
Deposited On:02 May 2018 07:31

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