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.

Biotech Sciences UCB Biopharma UK Slough SL1 3WE UK

Department of Physical and Macromolecular Chemistry Faculty of Science Charles University Prague 12843 Czech Republic

Global Chemistry UCB Biopharma UK Slough SL1 3WE UK

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 Eindhoven 5600 MB the Netherlands

Immuno Bone Discovery UCB Biopharma UK Slough SL1 3WE UK

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

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

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 Houston TX 77030 USA

Laboratory of Chemical Biology Department of Biomedical Engineering and Institute for Complex Molecular Systems Technische Universiteit Eindhoven Eindhoven 5600 MB the Netherlands

Protein Structure and Biophysics UCB Biopharma UK Slough SL1 3WE UK

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