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7qao

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Current revision

Three-dimensional structure of the PGAM5 C12S mutant TMD

Structural highlights

7qao is a 1 chain structure with sequence from Homo sapiens. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
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

The intramembrane protease PARL acts as a crucial mitochondrial safeguard by cleaving the mitophagy regulators PINK1 and PGAM5. Depending on the stress level, PGAM5 can either stimulate cell survival or cell death. In contrast to PINK1, which is constantly cleaved in healthy mitochondria and only active when the inner mitochondrial membrane is depolarized, PGAM5 processing is inversely regulated. However, determinants of PGAM5 that indicate it as a conditional substrate for PARL have not been rigorously investigated, and it is unclear how uncoupling the mitochondrial membrane potential affects its processing compared to that of PINK1. Here, we show that several polar transmembrane residues in PGAM5 distant from the cleavage site serve as key determinants for its PARL-catalyzed cleavage. Our NMR analysis indicates that a short N-terminal amphipathic helix, followed by a kink and a C-terminal transmembrane helix harboring the scissile peptide bond, are key for a productive interaction with PARL. Furthermore, we also show that PGAM5 is stably inserted into the inner mitochondrial membrane until uncoupling the membrane potential triggers its disassembly into monomers, which are then cleaved by PARL. In conclusion, we propose a model in which PGAM5 is slowly processed by PARL-catalyzed cleavage that is influenced by multiple hierarchical substrate features, including a membrane potential-dependent oligomeric switch.

Cleavage of mitochondrial homeostasis regulator PGAM5 by the intramembrane protease PARL is governed by transmembrane helix dynamics and oligomeric state.,Siebert V, Silber M, Heuten E, Muhle-Goll C, Lemberg MK J Biol Chem. 2022 Jul 31:102321. doi: 10.1016/j.jbc.2022.102321. PMID:35921890^[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
↑ Siebert V, Silber M, Heuten E, Muhle-Goll C, Lemberg MK. Cleavage of mitochondrial homeostasis regulator PGAM5 by the intramembrane protease PARL is governed by transmembrane helix dynamics and oligomeric state. J Biol Chem. 2022 Jul 31:102321. doi: 10.1016/j.jbc.2022.102321. PMID:35921890 doi:http://dx.doi.org/10.1016/j.jbc.2022.102321

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/7qao"

Categories: Homo sapiens | Large Structures | Muhle-Goll C | Silber M

@@ Line 1: / Line 1: @@
 ==Three-dimensional structure of the PGAM5 C12S mutant TMD==
-<StructureSection load='7qao' size='340' side='right'caption='[[7qao]], [[NMR_Ensembles_of_Models | 20 NMR models]]' scene=''>
+<StructureSection load='7qao' size='340' side='right'caption='[[7qao]]' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[7qao]] is a 1 chain structure. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7QAO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7QAO FirstGlance]. <br>
+<table><tr><td colspan='2'>[[7qao]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7QAO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7QAO FirstGlance]. <br>
-</td></tr><tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Phosphoprotein_phosphatase Phosphoprotein phosphatase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.3.16 3.1.3.16] </span></td></tr>
+</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7qao FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7qao OCA], [https://pdbe.org/7qao PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7qao RCSB], [https://www.ebi.ac.uk/pdbsum/7qao PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7qao ProSAT]</span></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7qao FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7qao OCA], [https://pdbe.org/7qao PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7qao RCSB], [https://www.ebi.ac.uk/pdbsum/7qao PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7qao ProSAT]</span></td></tr>
 </table>
 == Function ==
 [[https://www.uniprot.org/uniprot/PGAM5_HUMAN 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.<ref>PMID:18387606</ref> <ref>PMID:19590015</ref> <ref>PMID:22265414</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 22: / Line 21: @@
 __TOC__
 </StructureSection>
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Phosphoprotein phosphatase]]
+[[Category: Muhle-Goll C]]
-[[Category: Muhle-Goll, C]]
+[[Category: Silber M]]
-[[Category: Silber, M]]
-[[Category: Membrane protein]]
-[[Category: Mitochondria]]
-[[Category: Parl]]

7qao

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Current revision

Three-dimensional structure of the PGAM5 C12S mutant TMD

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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