Phosphatase Subfamily PGAM5
Phosphatase Classification: Fold HP: Superfamily HP (histidine phosphatase): HP, branch1 family: Subfamily PGAM5
PGAM5 is a mitochondrial protein phosphatase with multiple distinct substrates.
Evolution
PGAM5 is found in metazoa and many protists but is absent from fungi, plants, and amoebozoa.
Domain
Metazoan PGAM5 has a N-terminal transmembrane region and a HP1 phosphatase domain.
Functions
PGAM5 dephosphorylates and activates MAP kinase kinase kinase ASK1 (MAP3K5). PGAM5 is anchored in the mitochondrial membrane and it lacks mutase activity, but instead it associates with ASK1 and activates ASK1 by dephosphorylation of inhibitory sites. Mutation of an active site His-105 in PGAM5 abolished phosphatase activity with ASK1 and pThr peptides as substrates [1]. 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 [1].
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 [2].
Human PGAM5 also dephosphorylates FUNDC1 at Ser-13 and thereby activates mitophagy [3].
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.
References
- 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 |
- 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 |
- 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 |
