@article{f1bb74ca49bc4a98859d00cd527b405e,
title = "Capturing the Conformational Ensemble of the Mixed Folded Polyglutamine Protein Ataxin-3",
abstract = "Ataxin-3 is a deubiquitinase involved in protein quality control and other essential cellular functions. It preferentially interacts with polyubiquitin chains of four or more units attached to proteins delivered to the ubiquitin-proteasome system. Ataxin-3 is composed of an N-terminal Josephin domain and a flexible C terminus that contains two or three ubiquitin-interacting motifs (UIMs) and a polyglutamine tract, which, when expanded beyond a threshold, leads to protein aggregation and misfolding and causes spinocerebellar ataxia type 3. The high-resolution structure of the Josephin domain is available, but the structural and dynamical heterogeneity of ataxin-3 has so far hindered the structural description of the full-length protein. Here, we characterize non-expanded and expanded variants of ataxin-3 in terms of conformational ensembles adopted by the proteins in solution by jointly using experimental data from nuclear magnetic resonance and small-angle X-ray scattering with coarse-grained simulations. Our results pave the way to a molecular understanding of polyubiquitin recognition.",
keywords = "ensemble refinement, hybrid methods, intrinsically unfolded proteins, Monte Carlo simulations, neurodegeneration, NMR, polyglutamine, PRE, SAXS",
author = "Alessandro Sicorello and Bartosz R{\'o}{\.z}ycki and Konarev, {Petr V.} and Svergun, {Dmitri I.} and Annalisa Pastore",
note = "Funding Information: This research and A.S. were supported by the UK Dementia Research Institute ( RE1 3556 ) which is funded by the Medical Research Council , Alzheimer's Society , and Alzheimer{\textquoteright}s Research UK . We also acknowledge access to the MRC Biomedical NMR Center at the Francis Crick Institute . The Francis Crick Institute receives its core funding from Cancer Research UK ( FC001029 ), the UK Medical Research Council ( FC001029 ) and the Wellcome Trust ( FC001029 ). B.R. received support from the National Science Centre, Poland , grant no. 2016/21/B/NZ1/00006 . P.V.K. acknowledges the support from Ministry of Science and Higher Education of the Russian Federation within the State assignment FSRC “Crystallography and Photonics” RAS. Funding Information: This research and A.S. were supported by the UK Dementia Research Institute (RE1 3556) which is funded by the Medical Research Council, Alzheimer's Society, and Alzheimer's Research UK. We also acknowledge access to the MRC Biomedical NMR Center at the Francis Crick Institute. The Francis Crick Institute receives its core funding from Cancer Research UK (FC001029), the UK Medical Research Council (FC001029) and the Wellcome Trust (FC001029). B.R. received support from the National Science Centre, Poland, grant no. 2016/21/B/NZ1/00006. P.V.K. acknowledges the support from Ministry of Science and Higher Education of the Russian Federation within the State assignment FSRC ?Crystallography and Photonics? RAS. A.S. designed and carried out the experiments, and processed and analyzed the NMR data. B.R. performed the computer simulations. A.S. B.R. and P.V.K. processed, analyzed, and interpreted the SAXS data. D.I.S. provided advice on the analysis and interpretation of SAXS data. A.P. supervised the research. A.P. A.S. B.R. and P.V.K. wrote the manuscript. The authors declare absence of any conflict of interest. Publisher Copyright: {\textcopyright} 2020 Elsevier Ltd Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",
year = "2021",
month = jan,
day = "7",
doi = "10.1016/j.str.2020.09.010",
language = "English",
volume = "29",
pages = "70--81.e5",
journal = "Structure",
issn = "0969-2126",
publisher = "Cell Press",
number = "1",
}