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The Cul4‐DDB1‐WDR3/WDR6 complex binds SPAK and OSR1 kinases in a phosphorylation‐dependent manner

Dhiani, Binar Asrining and Mehellou, Youcef ORCID: 2020. The Cul4‐DDB1‐WDR3/WDR6 complex binds SPAK and OSR1 kinases in a phosphorylation‐dependent manner. ChemBioChem 21 (5) , pp. 638-643. 10.1002/cbic.201900454

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SPAK and OSR1 are two protein kinases that play critical roles in regulating ion homeostasis. They are activated under osmotic stress through phosphorylation by their upstream WNK kinases at a conserved threonine site on their T‐loops. Additionally, WNK kinases phosphorylate SPAK and OSR1 at a highly conserved serine residue on their S‐motif, the function of which remains elusive. Using affinity pull down and mass spectrometry, we identified the E3 ubiquitin ligase complex Cullin 4‐DDB1‐WDR3/WDR6 as a binder to OSR1 kinase in a SPAK/OSR1 S‐motif phosphorylation‐dependent manner. This binding was found to be compromised by S‐motif phosphorylation following osmotic stress. Using proteasomal and neddylation inhibitors, we subsequently showed that OSR1 ubiquitylation was abolished under osmotic stress when its S‐motif is phosphorylated. These results provide the first example of an E3 ubiquitin ligase system that binds the OSR1 kinase and, thus, links the CRL4 complex to ion homeostasis.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Subjects: R Medicine > RM Therapeutics. Pharmacology
Publisher: Wiley-Blackwell
ISSN: 1439-4227
Date of First Compliant Deposit: 29 October 2019
Date of Acceptance: 12 September 2019
Last Modified: 07 Nov 2023 20:52

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