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CDKL Family Kinases Have Evolved Distinct Structural Features and Ciliary Function

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 simila...

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Autores principales: Canning, Peter, Park, Kwangjin, Gonçalves, João, Li, Chunmei, Howard, Conor J., Sharpe, Timothy D., Holt, Liam J., Pelletier, Laurence, Bullock, Alex N., Leroux, Michel R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cell Press 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5846859/
https://www.ncbi.nlm.nih.gov/pubmed/29420175
http://dx.doi.org/10.1016/j.celrep.2017.12.083
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author Canning, Peter
Park, Kwangjin
Gonçalves, João
Li, Chunmei
Howard, Conor J.
Sharpe, Timothy D.
Holt, Liam J.
Pelletier, Laurence
Bullock, Alex N.
Leroux, Michel R.
author_facet Canning, Peter
Park, Kwangjin
Gonçalves, João
Li, Chunmei
Howard, Conor J.
Sharpe, Timothy D.
Holt, Liam J.
Pelletier, Laurence
Bullock, Alex N.
Leroux, Michel R.
author_sort Canning, Peter
collection PubMed
description 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.
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spelling pubmed-58468592018-03-13 CDKL Family Kinases Have Evolved Distinct Structural Features and Ciliary Function Canning, Peter Park, Kwangjin Gonçalves, João Li, Chunmei Howard, Conor J. Sharpe, Timothy D. Holt, Liam J. Pelletier, Laurence Bullock, Alex N. Leroux, Michel R. Cell Rep Article 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. Cell Press 2018-01-28 /pmc/articles/PMC5846859/ /pubmed/29420175 http://dx.doi.org/10.1016/j.celrep.2017.12.083 Text en © 2018 The Authors http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Canning, Peter
Park, Kwangjin
Gonçalves, João
Li, Chunmei
Howard, Conor J.
Sharpe, Timothy D.
Holt, Liam J.
Pelletier, Laurence
Bullock, Alex N.
Leroux, Michel R.
CDKL Family Kinases Have Evolved Distinct Structural Features and Ciliary Function
title CDKL Family Kinases Have Evolved Distinct Structural Features and Ciliary Function
title_full CDKL Family Kinases Have Evolved Distinct Structural Features and Ciliary Function
title_fullStr CDKL Family Kinases Have Evolved Distinct Structural Features and Ciliary Function
title_full_unstemmed CDKL Family Kinases Have Evolved Distinct Structural Features and Ciliary Function
title_short CDKL Family Kinases Have Evolved Distinct Structural Features and Ciliary Function
title_sort cdkl family kinases have evolved distinct structural features and ciliary function
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5846859/
https://www.ncbi.nlm.nih.gov/pubmed/29420175
http://dx.doi.org/10.1016/j.celrep.2017.12.083
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