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
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)
Published in Journal of Molecular Biology, Volume 433, Issue 19, 2021, pages 167174-.
© 2021 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/)
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