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Details on Person Phosphoglyceratemutase 5 (PGAM5) functions as a serine/threo...
| Class:Id | Summation:5364060 |
|---|---|
| _displayName | Phosphoglyceratemutase 5 (PGAM5) functions as a serine/threo... |
| _timestamp | 2014-09-29 16:03:34 |
| created | [InstanceEdit:5364231] Shamovsky, V, 2014-04-21 |
| literatureReference | [LiteratureReference:5364082] PGAM5 tethers a ternary complex containing Keap1 and Nrf2 to mitochondria [LiteratureReference:5357765] The mitochondrial phosphatase PGAM5 functions at the convergence point of multiple necrotic death pathways [LiteratureReference:5364089] The pseudokinase MLKL mediates necroptosis via a molecular switch mechanism [LiteratureReference:5364086] Depletion of RIPK3 or MLKL blocks TNF-driven necroptosis and switches towards a delayed RIPK1 kinase-dependent apoptosis [LiteratureReference:5364169] Mlkl knockout mice demonstrate the indispensable role of Mlkl in necroptosis [LiteratureReference:5357933] Plasma membrane translocation of trimerized MLKL protein is required for TNF-induced necroptosis [LiteratureReference:5357810] Diverse sequence determinants control human and mouse receptor interacting protein 3 (RIP3) and mixed lineage kinase domain-like (MLKL) interaction in necroptotic signaling [LiteratureReference:5364227] Necroptosis induced by RIPK3 requires MLKL but not Drp1 |
| modified | [InstanceEdit:5624569] Shamovsky, V, 2014-09-29 |
| text | Phosphoglyceratemutase 5 (PGAM5) functions as a serine/threonine-protein phosphatase, which was shown to localize to the outer membrane of mitochondria with its C terminus facing the cytoplasm (Lo SC and Hannink M 2008). RIP3 was found to associate with PGAM5 when immunoprecipitated from whole-cell extracts of RIP3-expressing HeLa cells under necrotic conditions (Wang Z et al. 2012). The association depended on kinase activity of RIP3 since a kinase-dead form of RIP3 (K50A) failed to precipitate PGAM5. The PGAM5:RIP3 association lead to phosphorylation of PGAM5. Furthermore, knockdown of mixed lineage kinase domain-like protein (MLKL) abolished PGAM5 phosphorylation. It has been suggested that RIP1:RIP3:MLKL-mediated enzymatic activation of PGAM5 may influence the fusion/fission equilibrium of mitochondria through dephosphorylation and activation of dynamin-1-like protein DNM1L (DRP1). Human PGAM5 exists as two splice variants, PGAM5L and PGAM5S. While knockdown of either isoform attenuated necrosis in HT29 and RIP3-expressing HeLa cells, PGAM5L and PGAM5S appeared to be differentially regulated. The necrosis-associated phosphorylation of PGAM5S did not occur in the presence of the necrosis inhibitor necrosulfonamide, whereas phosphorylation of PGAM5L and its binding to RIP3 was not affected (Wang Z et al. 2012). The authors suggested that PGAM5L leads the necrosome complex towards more hydrophobic PGAM5S on mitochondrial membrane and by this promotes the necrotic cell death via PGAM-DRP1 axis (Wang Z et al. 2012). It's important to note that the RIP3-mediated necrosis in human and mouse cells required RIP1, RIP3 and MLKL (Murphy JM et al. 2013; Wu J et al. 2013; Remijsen Q et al. 2014; Cai Z et al. 2014). However the downstream mechanism may differ between the two species as knockdown of PGAM5 and DNM1L did not protect mouse embryonic fibroblasts (MEFs) or L929 fibrosarcoma cells from the necrotic death (Moujalled DM et al. 2014; Remijsen Q et al. 2014; Chen W et al. 2013). |
| (summation) | [Reaction:5364104] RIPK1:RIPK3:MLKL binds PGAM5L [Homo sapiens] |
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