Soloviev, Zoja;
Bullock, Joshua MA;
James, Juliette MB;
Sauerwein, Andrea C;
Nettleship, Joanne E;
Owens, Raymond J;
Hansen, D Flemming;
... Thalassinos, Konstantinos; + view all
(2022)
Structural mass spectrometry decodes domain interaction and dynamics of the full-length Human Histone Deacetylase 2.
Biochimica et Biophysica Acta - Proteins and Proteomics
, 1870
(3)
, Article 140759. 10.1016/j.bbapap.2022.140759.
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Abstract
Human Histone Deacetylase 2 (HDAC2) belongs to a conserved enzyme superfamily that regulates deacetylation inside cells. HDAC2 is a drug target as it is known to be upregulated in cancers and neurodegenerative disorders. It consists of a globular deacetylase and C-terminus intrinsically-disordered domains [1-3]. To date, there is no full-length structure of HDAC2 available due to the high intrinsic flexibility of its C-terminal domain. The intrinsically-disordered domain, however, is known to be important for the enzymatic function of HDAC2 [1, 4]. Here we combine several structural Mass Spectrometry (MS) methodologies such as denaturing, native, ion mobility and chemical crosslinking, alongside biochemical assays and molecular modelling to study the structure and dynamics of the full-length HDAC2 for the first time. We show that MS can easily dissect heterogeneity inherent within the protein sample and at the same time probe the structural arrangement of the different conformers present. Activity assays combined with data from MS and molecular modelling suggest how the structural dynamics of the C-terminal domain, and its interactions with the catalytic domain, regulate the activity of this enzyme.
| Type: | Article |
|---|---|
| Title: | Structural mass spectrometry decodes domain interaction and dynamics of the full-length Human Histone Deacetylase 2 |
| Location: | Netherlands |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.bbapap.2022.140759 |
| Publisher version: | https://doi.org/10.1016/j.bbapap.2022.140759 |
| Language: | English |
| Additional information: | © 2022 The Authors. Published by Elsevier B.V. under a Creative Commons license (https://creativecommons.org/licenses/by/4.0/). |
| Keywords: | Crosslinking, Human Histone Deacetylase 2 (HDAC2), Intrinsically-disordered proteins, Ion Mobility Mass Spectrometry (IM-MS), Molecular modelling |
| UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Structural and Molecular Biology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10144955 |
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