Do metabolic HAD phosphatases moonlight as protein phosphatases?

Abstract

Mammalian haloacid dehalogenase (HAD)-type phosphatases have evolved to dephosphorylate a wide range of small metabolites, but can also target macromolecules such as serine/threonine, tyrosine-, and histidine-phosphorylated proteins. To accomplish these tasks, HAD phosphatases are equipped with cap domains that control access to the active site and provide substrate specificity determinants. A number of capped HAD phosphatases impact protein phosphorylation, although structural data are consistent with small metabolite substrates rather than protein substrates. This review discusses the structures, functions and disease implications of the three closely related, capped HAD phosphatases pyridoxal phosphatase (PDXP or chronophin), phosphoglycolate phosphatase (PGP, also termed AUM or glycerol phosphatase) and phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP or HDHD2B). Evidence in support of small metabolite and protein phosphatase activity is discussed in the context of the diversity of their biological functions.

Much More Than a Scaffold: Cytoskeletal Proteins in Neurological Disorders

“…In the case of chronophin, a mammalian haloacid dehalogenase (HAD)-type phosphatase, there is little knowledge of the direct regulation of its activity. However, available evidence shows that chronophin has a role in regulating actin dynamics at the leading edge of motile cells, (for a recent review of the research related to chronoipin, see [126]) and, more interestingly, that it seems to respond to the physiological levels of ATP in the cell [127]. Under normal levels of ATP, chronophin remains in a complex with the heat shock protein 90 (Hsp90), and, under the depletion of ATP, it is released of the complex and is therefore free to dephosphorylate cofilin.…”

NME/NM23/NDPK and Histidine Phosphorylation

“…can dephosphorylate low molecular weight compounds with P-N bonds, such as pHis, structural analysis of the LHPP. catalytic pocket suggests that pHis residues in proteins might be sterically restricted from gaining access to the active site ( [137]; R. Kaligiri, personal communication), in one sense analogous to the issue of how protein histidines gain access to the active site of NME. The molecular mechanism of LHPP.…”

Quest for the Crypto‐phosphoproteome

“…[80][81][82][83] LHPP, a HAD hydrolase that hydrolyzes protein pHis as well as pLys and inorganic pyrophosphate, [84] has a Ser for the second Asp in the HAD family signature motif hhhDxDx (Asp, Asp + 2) in the active site, posing questions about the role of the serine. [85] Another unanswered question is how the active site of LHPP can be accessible for macromolecular substrates, [86] as in the case of NDPKs. For pAsp phosphatases, bacterial HKs in TCS and auxiliary phosphatases such as CheZ and CheX can dephosphorylate pAsp in response regulators.…”