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A structural study of the cytoplasmic chaperone effect of 14-3-3 proteins on Ataxin-1
DOI:
10.1016/j.jmb.2021.167174
Authors:
Seppe
Leysen
(UCB Pharma)
,
Rebecca
Jane Burnley
(UCB Pharma)
,
Elizabeth
Rodriguez
(UCB Pharma)
,
Lech-Gustav
Milroy
(Technische Universiteit Eindhoven)
,
Lorenzo
Soini
(UCB Pharma; Technische Universiteit Eindhoven)
,
Carolyn J.
Adamski
(Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital; Baylor College of Medicine)
,
Larissa
Nitschke
(Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital; Baylor College of Medicine)
,
Rachel
Davis
(UCB Pharma)
,
Tomas
Obsil
(Charles University)
,
Lucas
Brunsveld
(Technische Universiteit Eindhoven)
,
Tom
Crabbe
(UCB Pharma)
,
Huda
Yahya Zoghbi
(Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital; Baylor College of Medicine)
,
Christian
Ottmann
(Technische Universiteit Eindhoven)
,
Jeremy
Martin Davis
(UCB Pharma)
Co-authored by industrial partner:
Yes
Type:
Journal Paper
Journal:
Journal Of Molecular Biology
, VOL 9
State:
Published (Approved)
Published:
July 2021

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.
Journal Keywords: neurodegeneration; protein aggregation; crystal structure; HDX-MS; SAXS
Diamond Keywords: Spinocerebellar Ataxia Type 1
Subject Areas:
Biology and Bio-materials
Instruments:
B21-High Throughput SAXS
Added On:
27/07/2021 09:42
Documents:
1-s2.0-S0022283621004071-main.pdf
Discipline Tags:
Neurodegenerative Diseases
Non-Communicable Diseases
Health & Wellbeing
Neurology
Structural biology
Biophysics
Life Sciences & Biotech
Technical Tags:
Scattering
Small Angle X-ray Scattering (SAXS)