https://doi.org/10.1016/j.jmb.2021.167174

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Author(s)

Seppe Leysen, Global Chemistry
Rebecca Jane Burnley, Protein Structure & Biophysics, UCB Biopharma UK
Elizabeth Rodriguez, Biotech Sciences, UCB Biopharma
Lech-Gustav Milroy, Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems, Technische Universiteit Eindhoven
Lorenzo Soini, Global Chemistry, UCB Biopharma UK, Slough SL1 3WE, UK; Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems, Technische Universiteit Eindhoven
Carolyn J. Adamski, Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Howard Hughes Medical Institute, Baylor College of Medicine
Larissa Nitschke, Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX, USA; Department of Molecular and Human Genetics, Baylor College of Medicine
Rachel Davis, University of South CarolinaFollow
Tomas Obsil, Department of Physical and Macromolecular Chemistry, Faculty of Science, Charles University
Lucas Brunsveld, Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems, Technische Universiteit Eindhoven
Tom Crabbe, Immuno-Bone Discovery, UCB Biopharma
Huda Yahya Zoghbi, Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA; Department of Neuroscience, Baylor College of Medicine
Christian Ottmann, Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems, Technische Universiteit Eindhoven
Jeremy Martin Davis, Global Chemistry, UCB Biopharma UK

Document Type

Article

Subject Area(s)

14-3-3 Proteins (metabolism); Ataxin-1 (chemistry, metabolism); Binding Sites; Cell Line; Crystallography, X-Ray; Cytoplasm (metabolism); HEK293 Cells; Humans; Phosphorylation; Protein Domains; Protein Multimerization; Protein Stability

Abstract

Expansion of the polyglutamine tract in the N terminus of Ataxin-1 is the main cause of the neurodegenerative disease, spinocerebellar ataxia type 1 (SCA1). However, the C-terminal part of the protein - including its AXH domain and a phosphorylation on residue serine 776 - also plays a crucial role in disease development. This phosphorylation event is known to be crucial for the interaction of Ataxin-1 with the 14-3-3 adaptor proteins and has been shown to indirectly contribute to Ataxin-1 stability. Here we show that 14-3-3 also has a direct anti-aggregation or "chaperone" effect on Ataxin-1. Furthermore, we provide structural and biophysical information revealing how phosphorylated S776 in the intrinsically disordered C terminus of Ataxin-1 mediates the cytoplasmic interaction with 14-3-3 proteins. Based on these findings, we propose that 14-3-3 exerts the observed chaperone effect by interfering with Ataxin-1 dimerization through its AXH domain, reducing further self-association. The chaperone effect is particularly important in the context of SCA1, as it was previously shown that a soluble form of mutant Ataxin-1 is the major driver of pathology.

Digital Object Identifier (DOI)

https://doi.org/10.1016/j.jmb.2021.167174

APA Citation

Leysen, S., Burnley, R., Rodriguez, E., Milroy, L., Soini, L., & Adamski, C. et al. (2021). A Structural Study of the Cytoplasmic Chaperone Effect of 14-3-3 Proteins on Ataxin-1. Journal Of Molecular Biology, 433(19), 167174. https://doi.org/10.1016/j.jmb.2021.167174

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