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Instruments / Technical Area	Publication Details	Published	Actions
I02-Macromolecular Crystallography I03-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength) I24-Microfocus Macromolecular Crystallography	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 Cell Reports 22, 885 - 894 DOI: 10.1016/j.celrep.2017.12.083 Diamond Proposal Number(s): [442, 6391, 8421] Open Access Show Abstract ▼ 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.	Jan 2018

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Publication Details

Published

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

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

Cell Reports 22, 885 - 894

DOI: 10.1016/j.celrep.2017.12.083

Diamond Proposal Number(s): [442, 6391, 8421]