6cni

From Proteopedia

Crystal structure of H105A PGAM5 dimer

Structural highlights

6cni 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 1.7Å
Ligands:	,
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]

Publication Abstract from PubMed

PGAM5 is a mitochondrial protein phosphatase whose genetic ablation in mice results in mitochondria-related disorders, including neurodegeneration. Functions of PGAM5 include regulation of mitophagy, cell death, metabolism and aging. However, mechanisms regulating PGAM5 activation and signaling are poorly understood. Using electron cryo-microscopy, we show that PGAM5 forms dodecamers in solution. We also present a crystal structure of PGAM5 that reveals the determinants of dodecamer formation. Furthermore, we observe PGAM5 dodecamer assembly into filaments both in vitro and in cells. We find that PGAM5 oligomerization into a dodecamer is not only essential for catalytic activation, but this form also plays a structural role on mitochondrial membranes, which is independent of phosphatase activity. Together, these findings suggest that modulation of the oligomerization of PGAM5 may be a regulatory switch of potential therapeutic interest.

Functional role of PGAM5 multimeric assemblies and their polymerization into filaments.,Ruiz K, Thaker TM, Agnew C, Miller-Vedam L, Trenker R, Herrera C, Ingaramo M, Toso D, Frost A, Jura N Nat Commun. 2019 Jan 31;10(1):531. doi: 10.1038/s41467-019-08393-w. PMID:30705304^[4]

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

References

↑ 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
↑ 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
↑ 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
↑ Ruiz K, Thaker TM, Agnew C, Miller-Vedam L, Trenker R, Herrera C, Ingaramo M, Toso D, Frost A, Jura N. Functional role of PGAM5 multimeric assemblies and their polymerization into filaments. Nat Commun. 2019 Jan 31;10(1):531. doi: 10.1038/s41467-019-08393-w. PMID:30705304 doi:http://dx.doi.org/10.1038/s41467-019-08393-w