CDKL family kinases have evolved distinct structural features and ciliary function

DOI: 10.1016/j.celrep.2017.12.083

Authors: Peter Canning (Structural Genomics Consortium, University of Oxford) , Kwangjin Park (Simon Fraser University) , João Gonçalves (Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital; University of Toronto) , Chunmei Li (Simon Fraser University) , Conor J. Howard (University of California) , Timothy D. Sharpe (Structural Genomics Consortium, University of Oxford) , Liam J. Holt (University of California) , Laurence Pelletier (Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital; University of Toronto) , Alex N. Bullock (Structural Genomics Consortium, University of Oxford) , Michel R. Leroux (Simon Fraser University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Cell Reports , VOL 22 , PAGES 885 - 894

State: Published (Approved)
Published: January 2018
Diamond Proposal Number(s): 442 , 6391 , 8421

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 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.

Journal Keywords: cilium length; Cyclin-Dependent Kinase-Like; CDKL; kinase; neurological disorder; protein structure

Subject Areas: Biology and Bio-materials


Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength) , I24-Microfocus Macromolecular Crystallography

Added On: 30/01/2018 15:52

Documents:
1-s2.0-S2211124717319204-main.pdf

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Neurology Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)