2. Academic Validation
  3. CDKL Family Kinases Have Evolved Distinct Structural Features and Ciliary Function

CDKL Family Kinases Have Evolved Distinct Structural Features and Ciliary Function

  • Cell Rep. 2018 Jan 23;22(4):885-894. doi: 10.1016/j.celrep.2017.12.083.
Peter Canning 1,  Kwangjin Park 2,  João Gonçalves 3,  Chunmei Li 2,  Conor J Howard 4,  Timothy D Sharpe 1,  Liam J Holt 4,  Laurence Pelletier 3,  Alex N Bullock 5,  Michel R Leroux 6
Affiliations

Affiliations

  • 1 Structural Genomics Consortium, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7DQ, UK.
  • 2 Department of Molecular Biology and Biochemistry, and Centre for Cell Biology, Development, and Disease, Simon Fraser University, 8888 University Drive, Burnaby, BC V5A 1S6, Canada.
  • 3 Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
  • 4 Department of Molecular & Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
  • 5 Structural Genomics Consortium, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7DQ, UK. Electronic address: [email protected].
  • 6 Department of Molecular Biology and Biochemistry, and Centre for Cell Biology, Development, and Disease, Simon Fraser University, 8888 University Drive, Burnaby, BC V5A 1S6, Canada. Electronic address: [email protected].
PMID: 29420175 DOI: 10.1016/j.celrep.2017.12.083
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.

Keywords

CDKL; Cyclin-Dependent Kinase-Like; cilium length; kinase; neurological disorder; protein structure.

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