3o0t

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Crystal structure of human phosphoglycerate mutase family member 5 (PGAM5) in complex with phosphate

Structural highlights

3o0t is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.9Å
Ligands:EDO, PO4
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

PGAM5_HUMAN Displays phosphatase activity for serine/threonine residues, and, dephosphorylates and activates MAP3K5 kinase. Has apparently no phosphoglycerate mutase activity. May be regulator of mitochondrial dynamics. Substrate for a KEAP1-dependent ubiquitin ligase complex. Contributes to the repression of NFE2L2-dependent gene expression. Acts as a central mediator for programmed necrosis induced by TNF, by reactive oxygen species and by calcium ionophore.[1] [2] [3]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

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.

Structures of PGAM5 Provide Insight into Active Site Plasticity and Multimeric Assembly.,Chaikuad A, Filippakopoulos P, Marcsisin SR, Picaud S, Schroder M, Sekine S, Ichijo H, Engen JR, Takeda K, Knapp S Structure. 2017 Jul 5;25(7):1089-1099.e3. doi: 10.1016/j.str.2017.05.020. Epub, 2017 Jun 22. PMID:28648608[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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See Also

References

  1. ↑ Lo SC, Hannink M. PGAM5 tethers a ternary complex containing Keap1 and Nrf2 to mitochondria. Exp Cell Res. 2008 May 1;314(8):1789-803. doi: 10.1016/j.yexcr.2008.02.014. Epub , 2008 Mar 5. PMID:18387606 doi:http://dx.doi.org/10.1016/j.yexcr.2008.02.014
  2. ↑ Takeda K, Komuro Y, Hayakawa T, Oguchi H, Ishida Y, Murakami S, Noguchi T, Kinoshita H, Sekine Y, Iemura S, Natsume T, Ichijo H. Mitochondrial phosphoglycerate mutase 5 uses alternate catalytic activity as a protein serine/threonine phosphatase to activate ASK1. Proc Natl Acad Sci U S A. 2009 Jul 28;106(30):12301-5. Epub 2009 Jul 9. PMID:19590015 doi:http://dx.doi.org/0901823106
  3. ↑ Wang Z, Jiang H, Chen S, Du F, Wang X. The mitochondrial phosphatase PGAM5 functions at the convergence point of multiple necrotic death pathways. Cell. 2012 Jan 20;148(1-2):228-43. doi: 10.1016/j.cell.2011.11.030. PMID:22265414 doi:http://dx.doi.org/10.1016/j.cell.2011.11.030
  4. ↑ Chaikuad A, Filippakopoulos P, Marcsisin SR, Picaud S, Schroder M, Sekine S, Ichijo H, Engen JR, Takeda K, Knapp S. Structures of PGAM5 Provide Insight into Active Site Plasticity and Multimeric Assembly. Structure. 2017 Jul 5;25(7):1089-1099.e3. doi: 10.1016/j.str.2017.05.020. Epub, 2017 Jun 22. PMID:28648608 doi:http://dx.doi.org/10.1016/j.str.2017.05.020

Contents


PDB ID 3o0t

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OCA

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