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Reference: Chaikuad, A, Filippakopoulos, P, Marcsisin, SR et al., (2017). Structures of PGAM5 provide insight into active site plasticity and multimeric assembly. Structure.Citable link to this page:

 

Structures of PGAM5 provide insight into active site plasticity and multimeric assembly.

Abstract: PGAM5 is a mitochondrial membrane protein that functions as an atypical Ser/Thr phosphatase and is a regulator of oxidative stress response, necroptosis, and autophagy. Here we present several crystal structures of PGAM5 including the activating N-terminal regulatory sequences, providing a model for structural plasticity, dimerization of the catalytic domain, and the assembly into an enzymatically active dodecameric form. Oligomeric states observed in structures were supported by hydrogen exchange mass spectrometry, size-exclusion chromatography, and analytical ultracentrifugation experiments in solution. We report that the catalytically important N-terminal WDPNWD motif acts as a structural integrator assembling PGAM5 into a dodecamer, allosterically activating the phosphatase by promoting an ordering of the catalytic loop. Additionally the observed active site plasticity enabled visualization of essential conformational rearrangements of catalytic elements. The comprehensive biophysical characterization offers detailed structural models of this key mitochondrial phosphatase that has been associated with the development of diverse diseases.

Publication status:PublishedPeer Review status:Peer reviewedVersion:Publisher's versionDate of acceptance:2017-05-24 Funder: Structural Genetics Consortium   Funder: AbbVie   Funder: Bayer Pharma AG   Funder: Boehringer Ingelheim   Funder: Canada Foundation for Innovation   Funder: Eshelman Institute for Innovation   Funder: Ontario Genomics Institute   Funder: Innovative Medicines Initiative   Funder: Janssen   Funder: Merck & Co.   Funder: Novartis Pharma AG   Funder: Ontario Ministry of Economic Development and Innovation   Funder: Pfizer   Funder: São Paulo Research Foundation   Funder: Takeda   Funder: Wellcome Trust   Funder: Waters Corporation   Funder: German Science Foundation   Funder: Center of Excellence Macromolecular   Notes:© 2017 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Bibliographic Details

Publisher: Elsevier

Publisher Website: http://www.elsevier.com/

Journal: Structuresee more from them

Publication Website: http://www.sciencedirect.com/science/journal/09692126

Issue Date: 2017-06Identifiers

Doi: https://doi.org/10.1016/j.str.2017.05.020

Eissn: 1878-4186

Issn: 0969-2126

Uuid: uuid:fb44c9b5-211e-4d95-a026-9215d5de7f13

Urn: uri:fb44c9b5-211e-4d95-a026-9215d5de7f13

Pubs-id: pubs:702399 Item Description

Type: journal-article;

Language: eng

Version: Publisher's versionKeywords: PGAM5 Ser/Thr phosphatase WDXNWD motif active site plasticity allosteric regulation catalysis histidine acid phosphatase oligomerization phosphoglycerate mutase

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Author: Chaikuad, A - Oxford, MSD, NDM, Structural Genomics Consortium - - - Filippakopoulos, P - Oxford, MSD, NDM, Structural Genomics C

Source: https://ora.ox.ac.uk/objects/uuid:fb44c9b5-211e-4d95-a026-9215d5de7f13



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