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Phosphoproteomic screening identifies physiological substrates of the CDKL5 kinase

Lookup NU author(s): Dr Julien Peltier, Professor Matthias TrostORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2018 The Authors. Published under the terms of the CC BY 4.0 license. Mutations in the gene encoding the protein kinase CDKL5 cause a debilitating neurodevelopmental disease termed CDKL5 disorder. The impact of these mutations on CDKL5 function is poorly understood because the substrates and cellular processes controlled by CDKL5 are unclear. Here, we describe a quantitative phosphoproteomic screening which identified MAP1S, CEP131 and DLG5—regulators of microtubule and centrosome function—as cellular substrates of CDKL5. Antibodies against MAP1S phospho-Ser900 and CEP131 phospho-Ser35 confirmed CDKL5-dependent phosphorylation of these targets in human cells. The phospho-acceptor serine residues in MAP1S, CEP131 and DLG5 lie in the motif RPXSA, although CDKL5 can tolerate residues other than Ala immediately C-terminal to the phospho-acceptor serine. We provide insight into the control of CDKL5 activity and show that pathogenic mutations in CDKL5 cause a major reduction in CDKL5 activity in vitro and in cells. These data reveal the first cellular substrates of CDKL5, which may represent important biomarkers in the diagnosis and treatment of CDKL5 disorder, and illuminate the functions of this poorly characterized kinase.

Publication metadata

Author(s): Munoz IM, Morgan ME, Peltier J, Weiland F, Gregorczyk M, Brown FCM, Macartney T, Toth R, Trost M, Rouse J

Publication type: Article

Publication status: Published

Journal: The EMBO Journal

Year: 2018

Volume: 37

Issue: 24

Print publication date: 14/12/2018

Online publication date: 28/09/2018

Acceptance date: 10/09/2018

Date deposited: 15/10/2018

ISSN (print): 0261-4189

ISSN (electronic): 1460-2075

Publisher: EMBO Press


DOI: 10.15252/embj.201899559


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