A conserved motif mediates both multimer formation and allosteric activation of phosphoglycerate mutase 5.

J Biol Chem

From the Bond Life Sciences Center and the Department of Biochemistry, University of Missouri, Columbia, Missouri 65211

Published: September 2014

AI Article Synopsis

  • PGAM5 is a special protein that helps with cell death and controls how mitochondria (the powerhouses of cells) work.
  • Researchers found that a specific part of PGAM5, called the WDXNWD motif, is really important for it to form big groups (multimeric complexes) and work well.
  • By changing or adding this WDXNWD part, they can either make PGAM5 work better or worse, which could help in discovering new medicines that affect this protein.

Article Abstract

Phosphoglycerate mutase 5 (PGAM5) is an atypical mitochondrial Ser/Thr phosphatase that modulates mitochondrial dynamics and participates in both apoptotic and necrotic cell death. The mechanisms that regulate the phosphatase activity of PGAM5 are poorly understood. The C-terminal phosphoglycerate mutase domain of PGAM5 shares homology with the catalytic domains found in other members of the phosphoglycerate mutase family, including a conserved histidine that is absolutely required for catalytic activity. However, this conserved domain is not sufficient for maximal phosphatase activity. We have identified a highly conserved amino acid motif, WDXNWD, located within the unique N-terminal region, which is required for assembly of PGAM5 into large multimeric complexes. Alanine substitutions within the WDXNWD motif abolish the formation of multimeric complexes and markedly reduce phosphatase activity of PGAM5. A peptide containing the WDXNWD motif dissociates the multimeric complex and reduces but does not fully abolish phosphatase activity. Addition of the WDXNWD-containing peptide in trans to a mutant PGAM5 protein lacking the WDXNWD motif markedly increases phosphatase activity of the mutant protein. Our results are consistent with an intermolecular allosteric regulation mechanism for the phosphatase activity of PGAM5, in which the assembly of PGAM5 into multimeric complexes, mediated by the WDXNWD motif, results in maximal activation of phosphatase activity. Our results suggest the possibility of identifying small molecules that function as allosteric regulators of the phosphatase activity of PGAM5.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4155678PMC
http://dx.doi.org/10.1074/jbc.M114.565549DOI Listing

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