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64  structures 1206  species 1  interaction 4055  sequences 54  architectures

Family: His_Phos_2 (PF00328)

Summary: Histidine phosphatase superfamily (branch 2)

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This is the Wikipedia entry entitled "Phosphatase". More...

Phosphatase Edit Wikipedia article

A phosphatase is an enzyme that removes a phosphate group from its substrate by hydrolysing phosphoric acid monoesters into a phosphate ion and a molecule with a free hydroxyl group (see dephosphorylation). This action is directly opposite to that of phosphorylases and kinases, which attach phosphate groups to their substrates by using energetic molecules like ATP. A common phosphatase in many organisms is alkaline phosphatase. Another large group of proteins present in archaea, bacteria, and eukaryote exhibits deoxyribonucleotide and ribonucleotide phosphatase or pyrophosphatase activities that catalyse the decomposition of dNTP/NTP into dNDP/NDP and a free phosphate ion or dNMP/NMP and a free pyrophosphate ion.[1][2][3]

Protein phosphorylation is one of the most common forms of reversible protein posttranslational modification (PTM), with up to 30% of all proteins being phosphorylated at any given time. Protein kinases (PKs) are the effectors of phosphorylation and catalyse the transfer of a γ-phosphate from ATP to specific amino acids on proteins. Several hundred PKs exist in mammals and are classified into distinct super-families. Proteins are phosphorylated predominantly on Ser, Thr and Tyr residues, which account for 86, 12 and 2% respectively of the phosphoproteome, at least in mammals. In contrast, protein phosphatases (PPs) are the primary effectors of dephosphorylation and can be grouped into three main classes based on sequence, structure and catalytic function. The largest class of PPs is the phosphoprotein phosphatase (PPP) family comprising PP1, PP2A, PP2B, PP4, PP5, PP6 and PP7, and the protein phosphatase Mg2+- or Mn2+-dependent (PPM) family, composed primarily of PP2C. The protein Tyr phosphatase (PTP) super-family forms the second group, and the aspartate-based protein phosphatases the third.

Mechanism

Cysteine-dependent phosphatases (CDPs) catalyse the hydrolysis of a phosphoester bond via a phospho-cysteine intermediate.[4]

Mechanism of Tyrosine dephosphorylation by a CDP

The free cysteine nucleophile forms a bond with the phosphorus atom of the phosphate moiety, and the P-O bond linking the phosphate group to the tyrosine is protonated, either by a suitably positioned acidic amino acid residue (Asp in the diagram below) or a water molecule. The phospho-cysteine intermediate is then hydrolysed by another water molecule, thus regenerating the active site for another dephosphorylation reaction.

Metallo-phosphatases (e.g. PP2C) co-ordinate 2 catalytically essential metal ions within their active site. There is currently some confusion of the identity of these metal ions, as successive attempts to identify them yield different answers. There is currently evidence that these metals could be Magnesium, Manganese, Iron, Zinc, or any combination thereof. It is thought that a hydroxyl ion bridging the two metal ions takes part in nucleophilic attack on the phosphorus ion.

Sub-types

Phosphatases can be subdivided based upon their substrate specificity.

Class Example Substrate Reference
Tyrosine-specific phosphatases PTP1B Phosphotyrosine [5]
Serine-/threonine-specific phosphatases PP2C (PPP2CA) Phosphoserine/-threonine [6]
Dual specificity phosphatases VHR, DUSP1DUSP28 Phosphotyrosine/-serine/-threonine [7]
Histidine phosphatase PHP Phospho-Histidine [8]
Lipid phosphatase PTEN Phosphatidyl-Inositol-3,4,5-Triphosphate [9]

Serine/threonine PP (PPM/PPP) families

Protein Ser/Thr phosphatases were originally classified using biochemical assays as either, type 1 (PP1) or type 2 (PP2), and were further subdivided based on metal-ion requirement (PP2A, no metal ion; PP2B, Ca2+ stimulated; PP2C, Mg2+ dependent) (Moorhead et al., 2007). The protein Ser/Thr phosphatases PP1, PP2A and PP2B of the PPP family, together with PP2C of the PPM family, account for the majority of Ser/Thr PP activity in vivo (Barford et al., 1998). In the brain, they are present in different subcellular compartments in neuronal and glial cells, and contribute to different neuronal functions.

PPM

The PPM family, which includes PP2C and pyruvate dehydrogenase phosphatase, are enzymes with Mn2+/Mg2+ metal ions that are resistant to classic inhibitors and toxins of the PPP family. Unlike most PPPs, PP2C exists in only one subunit but, like PTPs, it displays a wide variety of structural domains that confer unique functions. In addition, PP2C does not seem to be evolutionarily related to the major family of Ser/Thr PPs and has no sequence homology to ancient PPP enzymes. The current assumption is that PPMs evolved separately from PPPs but converged during evolutionary development.

Class I: Cys-based PTPs

Class I PTPs constitute the largest family. They contain the well-known classical receptor (a) and non-receptor PTPs (b), which are strictly tyrosine-specific, and the DSPs (c) which target Ser/Thr as well as Tyr and are the most diverse in terms of substrate specificity.

Class II: Cys-based LMW-PTPs

This class of PTPs is represented by a single gene in humans encoding the 18 kDa low MW phosphatase (LM-PTP/LMW-PTP). Related classes are widely distributed in living organisms and were highly conserved through evolution. The preservation of this class of phosphatases and the involvement of LMPTPs in many common diseases suggest that it is involved in the regulation of many fundamental processes in cellular physiology.

Class III: Cys-based PTPs

The third class of PTPs contains three cell cycle regulators, CDC25A, CDC25B and CDC25C, which dephosphorylate CDKs at their N-terminal, a reaction required to drive progression of the cell cycle. They are themselves regulated by phosphorylation and are degraded in response to DNA damage to prevent chromosomal abnormalities.

Class IV: Asp-based DSPs

The haloacid dehalogenase (HAD) superfamily is a further PP group that uses Asp as a nucleophile and was recently shown to have dual-specificity. These PPs can target both Ser and Tyr, but are thought to have greater specificity towards Tyr. A subfamily of HADs, the Eyes Absent Family (Eya), are also transcription factors and can therefore regulate their own phosphorylation and that of transcriptional cofactor/s, and contribute to the control of gene transcription. The combination of these two functions in Eya reveals a greater complexity of transcriptional gene control than previously thought . A further member of this class is the RNA polymerase II C-terminal domain phosphatase. While this family remains poorly understood, it is known to play important roles in development and nuclear morphology.

Physiological relevance

Phosphatases act in opposition to kinases/phosphorylases, which add phosphate groups to proteins. The addition of a phosphate group may activate or de-activate an enzyme (e.g., kinase signalling pathways[10]) or enable a protein-protein interaction to occur (e.g., SH2 domains [11]); therefore phosphatases are integral to many signal transduction pathways. It should be noted that phosphate addition and removal do not necessarily correspond to enzyme activation or inhibition, and that several enzymes have separate phosphorylation sites for activating or inhibiting functional regulation. CDK, for example, can be either activated or deactivated depending on the specific amino acid residue being phosphorylated. Phosphates are important in signal transduction because they regulate the proteins to which they are attached. To reverse the regulatory effect, the phosphate is removed. This occurs on its own by hydrolysis, or is mediated by protein phosphatases.

Protein phosphorylation plays a crucial role in biological functions and controls nearly every cellular process, including metabolism, gene transcription and translation, cell-cycle progression, cytoskeletal rearrangement, protein-protein interactions, protein stability, cell movement, and apoptosis. These processes depend on the highly regulated and opposing actions of PKs and PPs, through changes in the phosphorylation of key proteins. Histone phosphorylation, along with methylation, ubiquitination, sumoylation and acetylation, also regulates access to DNA through chromatin reorganisation.

One of the major switches for neuronal activity is the activation of PKs and PPs by elevated intracellular calcium. The degree of activation of the various isoforms of PKs and PPs is controlled by their individual sensitivities to calcium. Furthermore, a wide range of specific inhibitors and targeting partners such as scaffolding, anchoring, and adaptor proteins also contribute to the control of PKs and PPs and recruit them into signalling complexes in neuronal cells. Such signalling complexes typically act to bring PKs and PPs in close proximity with target substrates and signalling molecules as well as enhance their selectivity by restricting accessibility to these substrate proteins. Phosphorylation events, therefore, are controlled not only by the balanced activity of PKs and PPs but also by their restricted localisation. Regulatory subunits and domains serve to restrict specific proteins to particular subcellular compartments and to modulate protein specificity. These regulators are essential for maintaining the coordinated action of signalling cascades, which in neuronal cells include short-term (synaptic) and long-term (nuclear) signalling. These functions are, in part, controlled by allosteric modification by secondary messengers and reversible protein phosphorylation.

It is thought that around 30% of known PPs are present in all tissues, with the rest showing some level of tissue restriction. While protein phosphorylation is a cell-wide regulatory mechanism, recent quantitative proteomics studies have shown that phosphorylation preferentially targets nuclear proteins. Many PPs that regulate nuclear events, are often enriched or exclusively present in the nucleus. In neuronal cells, PPs are present in multiple cellular compartments and play a critical role at both pre- and post-synapses, in the cytoplasm and in the nucleus where they regulate gene expression.

Learning and memory

In the adult brain, PPs are essential for synaptic functions and are involved in the negative regulation of higher-order brain functions such as learning and memory. Dysregulation of their activity has been linked to several disorders including cognitive ageing and neurodegeneration, as well as cancer, diabetes and obesity.

See also

References

  1. ^ Davies O, Mendes P, Smallbone K, Malys N (2012). "Characterisation of multiple substrate-specific (d)ITP/(d)XTPase and modelling of deaminated purine nucleotide metabolism". BMB Reports 45 (4): 259–64. doi:10.5483/BMBRep.2012.45.4.259. PMID 22531138. 
  2. ^ Martin, S. S. and Senior, H. E. (1980). "Membrane adenosine triphosphatase activities in rat pancreas". Biochim. Biophys. Acta 602: 401–418. doi:10.1016/0005-2736(80)90320-x. PMID 6252965. 
  3. ^ Riley, M. V. and Peters, M. I. (1981). "The localization of the anion-sensitive ATPase activity in corneal endothelium". Biochim. Biophys. Acta 644: 251–256. doi:10.1016/0005-2736(81)90382-5. PMID 6114746. 
  4. ^ Barford D (November 1996). "Molecular mechanisms of the protein serine/threonine phosphatases". Trends Biochem. Sci. 21 (11): 407–12. doi:10.1016/S0968-0004(96)10060-8. PMID 8987393. 
  5. ^ Zhang ZY (2002). "Protein tyrosine phosphatases: structure and function, substrate specificity, and inhibitor development". Annu. Rev. Pharmacol. Toxicol. 42 (1): 209–34. doi:10.1146/annurev.pharmtox.42.083001.144616. PMID 11807171. 
  6. ^ Mumby MC, Walter G (October 1993). "Protein serine/threonine phosphatases: structure, regulation, and functions in cell growth". Physiol. Rev. 73 (4): 673–99. PMID 8415923. 
  7. ^ Camps M, Nichols A, Arkinstall S (January 2000). "Dual specificity phosphatases: a gene family for control of MAP kinase function". FASEB J. 14 (1): 6–16. PMID 10627275. 
  8. ^ Bäumer N, Mäurer A, Krieglstein J, Klumpp S (2007). "Expression of protein histidine phosphatase in Escherichia Coli, purification, and determination of enzyme activity". Methods Mol. Biol. 365: 247–60. doi:10.1385/1-59745-267-X:247. PMID 17200567. 
  9. ^ Maehama T, Okahara F, Kanaho Y (April 2004). "The tumour suppressor PTEN: involvement of a tumour suppressor candidate protein in PTEN turnover". Biochem. Soc. Trans. 32 (Pt 2): 343–7. doi:10.1042/BST0320343. PMID 15046605. 
  10. ^ Seger R, Krebs EG (June 1995). "The MAPK signaling cascade". FASEB J. 9 (9): 726–35. PMID 7601337. 
  11. ^ Ladbury JE (January 2007). "Measurement of the formation of complexes in tyrosine kinase-mediated signal transduction". Acta Crystallogr. D Biol. Crystallogr. 63 (Pt 1): 26–31. doi:10.1107/S0907444906046373. PMC 2483503. PMID 17164523. 

External links

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

Histidine phosphatase superfamily (branch 2) Provide feedback

The histidine phosphatase superfamily is so named because catalysis centres on a conserved His residue that is transiently phosphorylated during the catalytic cycle. Other conserved residues contribute to a 'phosphate pocket' and interact with the phospho group of substrate before, during and after its transfer to the His residue. Structure and sequence analyses show that different families contribute different additional residues to the 'phosphate pocket' and, more surprisingly, differ in the position, in sequence and in three dimensions, of a catalytically essential acidic residue. The superfamily may be divided into two main branches.The smaller branch 2 contains predominantly eukaryotic proteins. The catalytic functions in members include phytase, glucose-1-phosphatase and multiple inositol polyphosphate phosphatase. The in vivo roles of the mammalian acid phosphatases in branch 2 are not fully understood, although activity against lysophosphatidic acid and tyrosine-phosphorylated proteins has been demonstrated.

Literature references

  1. Kostrewa D, Wyss M, D'Arcy A, van Loon AP; , J Mol Biol 1999;288:965-974.: Crystal structure of Aspergillus niger pH 2.5 acid phosphatase at 2.4 A resolution. PUBMED:10329192 EPMC:10329192

  2. Rigden DJ;, Biochem J. 2008;409:333-348.: The histidine phosphatase superfamily: structure and function. PUBMED:18092946 EPMC:18092946


Internal database links

External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR000560

The histidine phosphatase superfamily is so named because catalysis centres on a conserved His residue that is transiently phosphorylated during the catalytic cycle. Other conserved residues contribute to a 'phosphate pocket' and interact with the phospho group of substrate before, during and after its transfer to the His residue. Structure and sequence analyses show that different families contribute different additional residues to the 'phosphate pocket' and, more surprisingly, differ in the position, in sequence and in three dimensions, of a catalytically essential acidic residue. The superfamily may be divided into two main branches. The relationship between the two branches is not evident by (PSI-)BLAST but is clear from more sensitive sequence searches and structural comparisons [PUBMED:18092946].

The smaller branch 2 contains predominantly eukaryotic proteins. The catalytic functions in members include phytase, glucose-1-phosphatase and multiple inositol polyphosphate phosphatase. The in vivo roles of the mammalian acid phosphatases in branch 2 are not fully understood, although activity against lysophosphatidic acid and tyrosine-phosphorylated proteins has been demonstrated.

Acid phosphatases (EC) are a heterogeneous group of proteins that hydrolyse phosphate esters, optimally at low pH. It has been shown [PUBMED:1989985] that a number of acid phosphatases, from both prokaryotes and eukaryotes, share two regions of sequence similarity, each centred around a conserved histidine residue. These two histidines seem to be involved in the enzymes' catalytic mechanism [PUBMED:8334986, PUBMED:1429631]. The first histidine is located in the N-terminal section and forms a phosphohistidine intermediate while the second is located in the C-terminal section and possibly acts as proton donor. Enzymes belonging to this family are called 'histidine acid phosphatases' and include:

Gene Ontology

The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.

Domain organisation

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Pfam Clan

This family is a member of clan His_phosphatase (CL0071), which has the following description:

The histidine phosphatase superfamily is so named because catalysis centres on a conserved His residue that is transiently phosphorylated during the catalytic cycle. Other conserved residues contribute to a 'phosphate pocket' and interact with the phospho group of substrate before, during and after its transfer to the His residue. Structure and sequence analyses show that different families contribute different additional residues to the 'phosphate pocket' and, more surprisingly, differ in the position, in sequence and in three dimensions, of a catalytically essential acidic residue. The superfamily may be divided into two main branches [1].

The clan contains the following 2 members:

His_Phos_1 His_Phos_2

Alignments

We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the NCBI sequence database, and our metagenomics sequence database. More...

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We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.

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(93)
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(4055)
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(41)
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(702)
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(1050)
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RP75
(1934)
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  Seed
(93)
Full
(4055)
Representative proteomes NCBI
(3581)
Meta
(41)
RP15
(702)
RP35
(1050)
RP55
(1602)
RP75
(1934)
Alignment:
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  Seed
(93)
Full
(4055)
Representative proteomes NCBI
(3581)
Meta
(41)
RP15
(702)
RP35
(1050)
RP55
(1602)
RP75
(1934)
Raw Stockholm Download   Download   Download   Download   Download   Download   Download   Download  
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You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

External links

MyHits provides a collection of tools to handle multiple sequence alignments. For example, one can refine a seed alignment (sequence addition or removal, re-alignment or manual edition) and then search databases for remote homologs using HMMER3.

HMM logo

HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...

Trees

This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.

Note: You can also download the data file for the tree.

Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation View help on the curation process

Seed source: Prosite
Previous IDs: acid_phosphat; Acid_phosphat_A;
Type: Family
Author: Finn RD, Griffiths-Jones SR, Rigden DJ
Number in seed: 93
Number in full: 4055
Average length of the domain: 323.30 aa
Average identity of full alignment: 15 %
Average coverage of the sequence by the domain: 63.62 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 20.3 20.3
Trusted cut-off 20.3 20.3
Noise cut-off 20.2 20.2
Model length: 347
Family (HMM) version: 17
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Species distribution

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Interactions

There is 1 interaction for this family. More...

His_Phos_2

Structures

For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the His_Phos_2 domain has been found. There are 64 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.

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