Mutational study of human phosphohistidine phosphatase: Effect on enzymatic activity

Ma, Ruixin; Kanders, Erik; Sundh, Ulla Beckman; Geng, Meiyu; Ek, Pia; Zetterqvist, Örjan; Li, Jinping

doi:10.1016/j.bbrc.2005.09.134

Cited by 26 publications

(24 citation statements)

References 24 publications

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“…1C). Two individual amino acid substitutions to alanine resulted in the loss of phosphatase activity (11). These mutations, His 53 3 Ala and His 102 3 Ala, map to this region of the enzyme.…”

Section: Resultsmentioning

confidence: 99%

“…Unlike most phosphatases it does not require divalent cations for activity. Individual point mutations of conserved histidine and arginine residues determined that Arg 45 , His 53 , and His 102 may play a role in the reaction mechanism as a result of eliminated or reduced phosphatase activity when mutated to alanines (11). PHPT1 is expressed in a variety of vertebrates but not in fungi or bacteria.…”

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confidence: 99%

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First Structure of a Eukaryotic Phosphohistidine Phosphatase

Busam

Thorsell

Flores

et al. 2006

Journal of Biological Chemistry

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Phosphatases are a diverse group of enzymes that regulate numerous cellular processes. Much of what is known relates to the tyrosine, threonine, and serine phosphatases, whereas the histidine phosphatases have not been studied as much. The structure of phosphohistidine phosphatase (PHPT1), the first identified eukaryotic-protein histidine phosphatase, has been determined to a resolution of 1.9 Å using multiple-wavelength anomalous dispersion methods. This enzyme can dephosphorylate a variety of proteins (e.g. ATP-citrate lyase and the ␤-subunit of G proteins). A putative active site has been identified by its electrostatic character, ion binding, and conserved protein residues. Histidine 53 is proposed to play a major role in histidine dephosphorylation based on these observations and previous mutational studies. Models of peptide binding are discussed to suggest possible mechanisms for substrate recognition.Reversible phosphorylation of residues is crucial in a variety of signaling pathways. Most of our understanding regarding these signaling events in eukaryotes comes from tyrosine, serine/threonine kinases, and phosphatases (1). Less well characterized is histidine phosphorylation-dependent signaling in eukaryotes. A little more than thirty years ago, Histone H4, the first vertebrate protein with a phosphorylated histidine residue, was identified (2). Since then there has been a measured increase in knowledge of mammalian histidine kinases (3). Unfortunately, very little information regarding eukaryotic histidine phosphatases has been available during this same period. This nescience is interesting because histidine phosphorylation is quite prevalent in the cell and likely accounts for ϳ6% of all phosphorylation in eukaryotes (4). Thus far, only one protein (the ␤-subunit of heterotrimeric G proteins) in vertebrates has been identified as undergoing reversible histidine phosphorylation where both the kinase (NDPK B) and phosphatase (PHPT1) 2 are known (for a recent review, see Ref. 5). However, more information regarding histidine phosphatases is slowly beginning to emerge. To date, the only other structure of a histidine phosphatase is Escherichia coli SixA (6). Under certain anaerobic respiratory conditions, SixA is involved in down-regulation of the E. coli ArcB-to-ArcA phosphorelay system. SixA shows structural homology to the well studied family of arginine-histidine-glycine (RHG) phosphatases (6) but no sequence homology to PHPT1.Mammalian phosphohistidine phosphatase (PHPT1) was first identified and characterized as a 14-kDa protein in 2002 (7,8). The enzyme can dephosphorylate the phosphohistidinecontaining peptide succinyl-Ala-His(P)-Pro-Phe-p-nitroanilide, E. coli cheA, rabbit ATP-citrase lyase, and the rat ␤-subunit of G proteins (7-10). PHPT1 has been suggested to be highly involved in neuronal function. Unlike most phosphatases it does not require divalent cations for activity. Individual point mutations of conserved histidine and arginine residues determined that Arg 45 , His 53 , and His 102 ma...

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

First Structure of a Eukaryotic Phosphohistidine Phosphatase

Busam

Thorsell

Flores

et al. 2006

Journal of Biological Chemistry

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“…It is found that PHPT1 is ubiquitously expressed in eukaryotic species from Caenorhabditis elegans to Homo sapien (Klumpp et al 2002). The primary sequences of PHPT1 are also fairly conserved in the animal kingdom (Ma et al 2005). In addition, ATP-citrate lyase and the b-subunit of G-proteins are found to be its potential substrates, indicating its function in metabolism and signal transduction (Maurer et al 2005;Klumpp et al 2003).…”

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confidence: 97%

“…Therefore, PHPT1 probably plays an important biological role. Recent site-specific mutagenesis and crystallography studies have revealed the three-dimensional structure of PHPT1 and provided information about its active site (Busam et al 2006;Ma et al 2005). In order to determine the solution structure and study its interaction with substrate proteins, we herein report the nearly complete sequencespecific backbone and side-chain NMR assignments of human PHPT1.…”

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confidence: 98%

1H, 13C, and 15N resonance assignments of human phosphohistidine phosphatase 1 (PHPT1)

et al. 2007

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“…28 In this particular case, it is not clear which isomer of pHis is formed and on which His residue. Mammalian pHis phosphatases, which have been characterized include: protein pHis phosphatase 1 (PHPT1); 17,[29][30][31][32][33][34][35] Lys/His phosphatase (LHPPase); 36,37 Ser Thr protein phosphatases (PP1/2 A/2C); 38,39 T-cell ubiquitin ligand-2 (TULA-2); 40,41 and the recently reported phosphoglycerate mutase-5 (PGAM5). 42 In addition, pHis phosphatase activity has been reported in rat tissue extracts but these have not been fully characterized.…”

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confidence: 99%

Advances in development of new tools for the study of phosphohistidine

Makwana

Muimo

Jackson

2018

Laboratory Investigation

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Protein phosphorylation is an important post-translational modification that is an integral part of cellular function. The O-phosphorylated amino-acid residues, such as phosphoserine (pSer), phosphothreonine (pThr) and phosphotyrosine (pTyr), have dominated the literature while the acid labile N-linked phosphorylated amino acids, such as phosphohistidine (pHis), have largely been historically overlooked because of the acidic conditions routinely used in amino-acid detection and analysis. This review highlights some misinterpretations that have arisen in the existing literature, pinpoints outstanding questions and potential future directions to clarify the role of pHis in mammalian signalling systems. Particular emphasis is placed on pHis isomerization and the hybrid functionality for both pHis and pTyr of the proposed τ-pHis analogue bearing the triazole residue.

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Mutational study of human phosphohistidine phosphatase: Effect on enzymatic activity

Cited by 26 publications

References 24 publications

First Structure of a Eukaryotic Phosphohistidine Phosphatase

First Structure of a Eukaryotic Phosphohistidine Phosphatase

1H, 13C, and 15N resonance assignments of human phosphohistidine phosphatase 1 (PHPT1)

Advances in development of new tools for the study of phosphohistidine

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