Phosphatase Subfamily PGAM5

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Phosphatase Classification: Fold HP: Superfamily HP: HP, branch1 family: Subfamily PGAM5

PGAM5 is a mitochondrial protein serine phosphatase with multiple distinct substrates.


PGAM5 is found in metazoa and many protists but is absent from fungi, plants, and amoebozoa.


Metazoan PGAM5 has a N-terminal mitochondria targeting sequence localizes PGAM5 to inner mitochondria membrane [1] and a HP1 phosphatase domain.


PGAM5 is anchored in the mitochondrial membrane [1, 2]. It functions as phosphatase rather than mutase. Its substrates include:

  • ASK1 (MAP3K5). PGAM5 dephosphorylates and activates MAP kinase kinase kinase ASK1 (MAP3K5). Mutation of an active site His-105 in PGAM5 abolished phosphatase activity with ASK1 and pThr peptides as substrates [2]. The Drosophila and Caenorhabditis elegans orthologs of PGAM5 also exhibit specific Ser/Thr phosphatase activity and activate the corresponding Drosophila and C. elegans ASK1 kinases [2]. The authors of [2] have tried but failed to find out the substrate residues of ASK1. They ruled out the possibility of Ser-83, Ser-966, and Ser-1033, though.
  • Drp1 (DNM1L). PGAM5 also dephosphorylates the Ser-637 site of the GTPase Drp1 (DNM1L, dynamin 1-like) as a member of a RIP1- and RIP3-containing protein complex in response to necrosis induction. The dephosphorylation activates the GTPase activity of Drp1 and causes mitochondrial fragmentation, an early and obligatory step for necrosis [3].
  • FUNDC1. Human PGAM5 also dephosphorylates FUNDC1 at Ser-13 and thereby activates mitophagy [4].

PGAM5 is activated by RIPK3 in the immune responses to tumours and liver inflammation mediated by natural killer T-cells [5].

PGAM5 is specifically expressed in testis, according to GTEx. Its known substrates do not have similar tissue-specific expression pattern according to GTEx data: ASK1 (MAP3K5) is widely expressed, most abundant in adrenal gland and ovary; Drp1 (DNM1L) is widely expressed, most abundant in brain; FUNDC1 is also widely expressed in different tissues.


  1. Sekine S, Kanamaru Y, Koike M, Nishihara A, Okada M, Kinoshita H, Kamiyama M, Maruyama J, Uchiyama Y, Ishihara N, Takeda K, and Ichijo H. Rhomboid protease PARL mediates the mitochondrial membrane potential loss-induced cleavage of PGAM5. J Biol Chem. 2012 Oct 5;287(41):34635-45. DOI:10.1074/jbc.M112.357509 | PubMed ID:22915595 | HubMed [Sekine12]
  2. Takeda K, Komuro Y, Hayakawa T, Oguchi H, Ishida Y, Murakami S, Noguchi T, Kinoshita H, Sekine Y, Iemura S, Natsume T, and 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. DOI:10.1073/pnas.0901823106 | PubMed ID:19590015 | HubMed [PGAM5_1]
  3. Wang Z, Jiang H, Chen S, Du F, and 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 | PubMed ID:22265414 | HubMed [PGAM5_2]
  4. Chen G, Han Z, Feng D, Chen Y, Chen L, Wu H, Huang L, Zhou C, Cai X, Fu C, Duan L, Wang X, Liu L, Liu X, Shen Y, Zhu Y, and Chen Q. A regulatory signaling loop comprising the PGAM5 phosphatase and CK2 controls receptor-mediated mitophagy. Mol Cell. 2014 May 8;54(3):362-77. DOI:10.1016/j.molcel.2014.02.034 | PubMed ID:24746696 | HubMed [chen14]
  5. Kang YJ, Bang BR, Han KH, Hong L, Shim EJ, Ma J, Lerner RA, and Otsuka M. Regulation of NKT cell-mediated immune responses to tumours and liver inflammation by mitochondrial PGAM5-Drp1 signalling. Nat Commun. 2015 Sep 18;6:8371. DOI:10.1038/ncomms9371 | PubMed ID:26381214 | HubMed [Kang15]
All Medline abstracts: PubMed | HubMed