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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




Journal article



Publication Date





1089 - 1099.e3


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