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)