Pseudophosphorylation of single residues of the J-domain of DNAJA2 regulates the holding/folding balance of the Hsc70 system.

Autor: Velasco-Carneros L; Instituto Biofisika (UPV/EHU, CSIC), University of Basque Country, Leioa, Spain.; Department of Biochemistry and Molecular Biology, Faculty of Science and Technology, University of the Basque Country (UPV/EHU), Leioa, Spain., Bernardo-Seisdedos G; Precision Medicine and Metabolism Lab, CIC bioGUNE, Derio, Spain.; Department of Medicine, Faculty of Health Sciences, University of Deusto, Bilbao, Spain., Maréchal JD; Insilichem, Departament de Química, Universitat Autònoma de Barcelona (UAB), Bellaterra (Barcelona), Spain., Millet O; Precision Medicine and Metabolism Lab, CIC bioGUNE, Derio, Spain., Moro F; Instituto Biofisika (UPV/EHU, CSIC), University of Basque Country, Leioa, Spain.; Department of Biochemistry and Molecular Biology, Faculty of Science and Technology, University of the Basque Country (UPV/EHU), Leioa, Spain., Muga A; Instituto Biofisika (UPV/EHU, CSIC), University of Basque Country, Leioa, Spain.; Department of Biochemistry and Molecular Biology, Faculty of Science and Technology, University of the Basque Country (UPV/EHU), Leioa, Spain.
Jazyk: angličtina
Zdroj: Protein science : a publication of the Protein Society [Protein Sci] 2024 Aug; Vol. 33 (8), pp. e5105.
DOI: 10.1002/pro.5105
Abstrakt: The Hsp70 system is essential for maintaining protein homeostasis and comprises a central Hsp70 and two accessory proteins that belong to the J-domain protein (JDP) and nucleotide exchange factor families. Posttranslational modifications offer a means to tune the activity of the system. We explore how phosphorylation of specific residues of the J-domain of DNAJA2, a class A JDP, regulates Hsc70 activity using biochemical and structural approaches. Among these residues, we find that pseudophosphorylation of Y10 and S51 enhances the holding/folding balance of the Hsp70 system, reducing cochaperone collaboration with Hsc70 while maintaining the holding capacity. Truly phosphorylated J domains corroborate phosphomimetic variant effects. Notably, distinct mechanisms underlie functional impacts of these DNAJA2 variants. Pseudophosphorylation of Y10 induces partial disordering of the J domain, whereas the S51E substitution weakens essential DNAJA2-Hsc70 interactions without a large structural reorganization of the protein. S51 phosphorylation might be class-specific, as all cytosolic class A human JDPs harbor a phosphorylatable residue at this position.
(© 2024 The Author(s). Protein Science published by Wiley Periodicals LLC on behalf of The Protein Society.)
Databáze: MEDLINE
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