CDKL Family Kinases Have Evolved Distinct Structural Features and Ciliary Function
Peter Canning,
Kwangjin Park,
João Gonçalves,
Chunmei Li,
Conor J. Howard,
Timothy D. Sharpe,
Liam J. Holt,
Laurence Pelletier,
Alex N. Bullock,
Michel R. Leroux
Affiliations
Peter Canning
Structural Genomics Consortium, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7DQ, UK
Kwangjin Park
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
João Gonçalves
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON M5G 1X5, Canada
Chunmei Li
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
Conor J. Howard
Department of Molecular & Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA
Timothy D. Sharpe
Structural Genomics Consortium, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7DQ, UK
Liam J. Holt
Department of Molecular & Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA
Laurence Pelletier
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON M5G 1X5, Canada
Alex N. Bullock
Structural Genomics Consortium, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7DQ, UK
Michel R. Leroux
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
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 αJ 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 αJ 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.
