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.

• Klíčová slova
• HDX-MS, SAXS, crystal structure, neurodegeneration, protein aggregation,
• MeSH
• ataxin-1 chemie   metabolismus   MeSH
• buněčné linie MeSH
• cytoplazma metabolismus   MeSH
• fosforylace MeSH
• HEK293 buňky MeSH
• krystalografie rentgenová MeSH
• lidé MeSH
• multimerizace proteinu MeSH
• proteinové domény MeSH
• proteiny 14-3-3 metabolismus   MeSH
• stabilita proteinů MeSH
• vazebná místa MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• ataxin-1 MeSH
• ATXN1 protein, human MeSH Prohlížeč
• proteiny 14-3-3 MeSH