The mitochondrial protein phosphatase PGAM5, which presents as two splice variants, PGAM5L (long form) and PGAM5S (short form) (1), acts as a specific protein Ser/Thr phosphatase, that activates ASK1 by dephosphorylation of inhibitory sites. Mutation of an active site His-105 in PGAM5 abolished phosphatase activity with ASK1 and phospho-Thr peptides as substrates. 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). PGAM5 also belongs to the histidine phosphatase superfamily, that shares a conserved catalytic core centred on a histidine which is phosphorylated during the course of the reaction (3). Panda, et al., show that phosphoglycerate mutase family 5 (PGAM5) is also a phosphohistidine phosphatase (4).

Reference
1. Wang Z, Jiang H, Chen S, Du F, Wang X. (2012) The mitochondrial phosphatase PGAM5 functions at the convergence point of multiple necrotic death pathways. Cell, 148(1-2), 228-43. PMID: 22265414
2. Takeda K, Komuro Y, Hayakawa T, Oguchi H, Ishida Y, Murakami S, Noguchi T, Kinoshita H, Sekine Y, Iemura S, Natsume T, Ichijo H. (2009) Mitochondrial phosphoglycerate mutase 5 uses alternate catalytic activity as a protein serine/threonine phosphatase to activate ASK1. Proc Natl Acad Sci U S A, 106(30), 12301-5. PMID: 19590015
3. Rigden DJ. (2008) The histidine phosphatase superfamily: structure and function. Biochem J, 409(2), 333-48. PMID: 18092946
4. Panda S, Srivastava S, Li Z, Vaeth M, Fuhs SR, Hunter T, Skolnik EY. (2016) Identification of PGAM5 as a Mammalian Protein Histidine Phosphatase that Plays a Central Role to Negatively Regulate CD4(+) T Cells.. Mol Cell, 63(3), 457-69. PMID: 27453048