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 mitochondria targeting sequence localizes PGAM5 to inner mitochondria membrane [1] and a HP1 phosphatase domain.

Functions

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 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

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