Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

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.

Original publication

DOI

10.1016/j.str.2017.05.020

Type

Journal article

Journal

Structure

Publication Date

05/07/2017

Volume

25

Pages

1089 - 1099.e3

Keywords

PGAM5, Ser/Thr phosphatase, WDXNWD motif, active site plasticity, allosteric regulation, catalysis, histidine acid phosphatase, oligomerization, phosphoglycerate mutase, Allosteric Regulation, Allosteric Site, Catalytic Domain, HEK293 Cells, Humans, Mitochondrial Proteins, Molecular Dynamics Simulation, Phosphoprotein Phosphatases, Protein Multimerization