Letunic et al. (2017) Nucleic Acids Res doi: 10.1093/nar/gkx922
Letunic et al. (2020) Nucleic Acids Res doi: 10.1093/nar/gkaa937

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POLIIIAc DNA polymerase alpha chain like domain

SMART accession number:	SM00481
Description:	DNA polymerase alpha chain like domain, incl. family of hypothetical proteins
Interpro abstract (IPR003141):	This domain is associated with the N terminus of members of the PHP superfamily, this includes: subunit of bacterial DNA polymerase III, eukaryotic DNA polymerase, X-family of DNA polymerases, histidinol phosphatases, and a number of uncharacterised protein families. In common for all PHP proteins is the presence of four conserved sequence motifs that contain invariant histidine and aspartate residues implicated in metal ion coordination. As part of DNA polymerases, the PHP domain was suggested to hydrolyse pyrophosphate and thereby shift the reaction equilibrium toward nucleotide polymerisation. However, it cannot be ruled out that the PHP domain possesses a nuclease activity, particularly in the repair polymerases of the X-family. No functional information is available for standalone proteins that belong to the PHP superfamily. The crystal structure of the YcdX protein from Escherichia coli has been determined to 1.6-A resolution. YcdX has an unusual topology of a alpha 7_beta 7 barrel compared with the more common alpha 8_beta 8 (TIM) barrel. The C-terminal helix caps the barrel on the N-terminal side. The deep cleft at the C-terminal side of the barrel contains the three zinc binding residues. These residues are invariant in the YcdX family confirming their functional importance. Only four proteins with known structures have a similar trinuclear zinc catalytic site. All four (nuclease P1, endonuclease IV, alkaline phosphatase, and phospholipase C) hydrolyse the phosphoester bond. This finding suggests a similar activity for YcdX. YcdX is among the genes significantly induced in response to the DNA damage, therefore indicating that members of the YcdX family may be involved in DNA repair [ (PUBMED:12661000) ].
Family alignment:	View or CHROMA formatHMM/Web logoCLUSTALW formatMSF formatFASTA formatPIR format

There are 65575 POLIIIAc domains in 65574 proteins in SMART's nrdb database.

Click on the following links for more information.

• Evolution (species in which this domain is found)

• Taxonomic distribution of proteins containing POLIIIAc domain.

  This tree includes only several representative species. The complete taxonomic breakdown of all proteins with POLIIIAc domain is also avaliable.

  Click on the protein counts, or double click on taxonomic names to display all proteins containing POLIIIAc domain in the selected taxonomic class.

• Cellular role (predicted cellular role)

• Cellular role: replication
  

• Literature (relevant references for this domain)

• Primary literature is listed below; Automatically-derived, secondary literature is also avaliable.

  • Aravind L, Koonin EV
  • Phosphoesterase domains associated with DNA polymerases of diverse origins.
  • Nucleic Acids Res. 1998; 26: 3746-52
  • Display abstract

  • Computer analysis of DNA polymerase protein sequences revealed previously unidentified conserved domains that belong to two distinct superfamilies of phosphoesterases. The alpha subunits of bacterial DNA polymerase III and two distinct family X DNA polymerases are shown to contain an N-terminal domain that defines a novel enzymatic superfamily, designated PHP, after polymerase and histidinol phosphatase. The predicted catalytic site of the PHP superfamily consists of four motifs containing conserved histidine residues that are likely to be involved in metal-dependent catalysis of phosphoester bond hydrolysis. The PHP domain is highly conserved in all bacterial polymerase III alpha subunits, but in proteobacteria and mycoplasmas, the conserved motifs are distorted, suggesting a loss of the enzymatic activity. Another conserved domain, found in the small subunits of archaeal DNA polymerase II and eukaryotic DNA polymerases alpha and delta, is shown to belong to the superfamily of calcineurin-like phospho-esterases, which unites a variety of phosphatases and nucleases. The conserved motifs required for phospho-esterase activity are intact in the archaeal DNA polymerase subunits, but are disrupted in their eukaryotic orthologs. A hypothesis is proposed that bacterial and archaeal replicative DNA polymerases possess intrinsic phosphatase activity that hydrolyzes the pyrophosphate released during nucleotide polymerization. As proposed previously, pyrophosphate hydrolysis may be necessary to drive the polymerization reaction forward. The phosphoesterase domains with disrupted catalytic motifs may assume an allosteric, regulatory function and/or bind other subunits of DNA polymerase holoenzymes. In these cases, the pyrophosphate may be hydrolyzed by a stand-alone phosphatase, and candidates for such a role were identified among bacterial PHP superfamily members.

• Metabolism (metabolic pathways involving proteins which contain this domain)

• Click the image to view the interactive version of the map in iPath

  % proteins involved KEGG pathway ID Description 96.81 map03030 DNA replication 1.95 map00340 Histidine metabolism 0.35 map00020 Citrate cycle (TCA cycle) 0.35 map00720 Reductive carboxylate cycle (CO2 fixation) 0.18 map00970 Aminoacyl-tRNA biosynthesis 0.18 map00400 Phenylalanine, tyrosine and tryptophan biosynthesis 0.18 map00290 Valine, leucine and isoleucine biosynthesis This information is based on mapping of SMART genomic protein database to KEGG orthologous groups. Percentage points are related to the number of proteins with POLIIIAc domain which could be assigned to a KEGG orthologous group, and not all proteins containing POLIIIAc domain. Please note that proteins can be included in multiple pathways, ie. the numbers above will not always add up to 100%.

• Structure (3D structures containing this domain)

• 3D Structures of POLIIIAc domains in PDB

  PDB code	Main view	Title
  1m65		YCDX PROTEIN
  1m68		YCDX PROTEIN, TRINUCLEAR ZINC SITE
  1pb0		YCDX PROTEIN IN AUTOINHIBITED STATE
  2anu		Crystal structure of Predicted metal-dependent phosphoesterase (PHP family) (tm0559) from THERMOTOGA MARITIMA at 2.40 A resolution
  2hnh		Crystal structure of the catalytic alpha subunit of E. coli replicative DNA polymerase III
  2hpi		Eubacterial and Eukaryotic Replicative DNA Polymerases are not Homologous: X-ray Structure of DNA Polymerase III
  2hpm		Eubacterial and Eukaryotic Replicative DNA Polymerases are not Homologous: X-ray Structure of DNA Polymerase III
  2hqa		Crystal structure of the catalytic alpha subunit of E. Coli replicative DNA polymerase III
  2w9m		Structure of family X DNA polymerase from Deinococcus radiodurans
  2yb1		Structure of an amidohydrolase from Chromobacterium violaceum (EFI target EFI-500202) with bound Mn, AMP and phosphate.
  2yb4		Structure of an amidohydrolase from Chromobacterium violaceum (EFI target EFI-500202) with bound SO4, no metal
  2yxo		Histidinol Phosphate Phosphatase complexed with Sulfate
  2yz5		Histidinol Phosphate Phosphatase complexed with Phosphate
  2z4g		Histidinol Phosphate Phosphatase from Thermus thermophilus HB8
  3au2		DNA polymerase X from Thermus thermophilus HB8 complexed with Ca-dGTP
  3au6		DNA polymerase X from Thermus thermophilus HB8 ternary complex with primer/template DNA and ddGTP
  3auo		DNA polymerase X from Thermus thermophilus HB8 ternary complex with 1-nt gapped DNA and ddGTP
  3b0x		K263A mutant of PolX from Thermus thermophilus HB8 complexed with Ca-dGTP
  3b0y		K263D mutant of PolX from Thermus thermophilus HB8 complexed with Ca-dGTP
  3e0d		Insights into the Replisome from the Crystral Structure of the Ternary Complex of the Eubacterial DNA Polymerase III alpha-subunit
  3e0f		Crystal structure of a putative metal-dependent phosphoesterase (bad_1165) from bifidobacterium adolescentis atcc 15703 at 2.40 A resolution
  3e38		CRYSTAL STRUCTURE OF A TWO-DOMAIN PROTEIN CONTAINING PREDICTED PHP-LIKE METAL-DEPENDENT PHOSPHOESTERASE (BVU_3505) FROM BACTEROIDES VULGATUS ATCC 8482 AT 2.20 A RESOLUTION
  3f2b		DNA Polymerase PolC from Geobacillus kaustophilus complex with DNA, dGTP, Mg and Zn
  3f2c		DNA Polymerase PolC from Geobacillus kaustophilus complex with DNA, dGTP and Mn
  3f2d		DNA Polymerase PolC from Geobacillus kaustophilus complex with DNA, dGTP, Mn and Zn
  3o0f		Crystal structure of a putative metal-dependent phosphoesterase (BAD_1165) from bifidobacterium adolescentis atcc 15703 at 1.94 A resolution
  4gc3		Crystal structure of L-HISTIDINOL PHOSPHATE PHOSPHATASE (HISK) from Lactococcus lactis subsp. lactis Il1403 complexed with ZN and sulfate
  4gk8		Crystal structure of histidinol phosphate phosphatase (HISK) from Lactococcus lactis subsp. lactis Il1403 complexed with ZN and L-histidinol arsenate
  4gx8		Crystal structure of a DNA polymerase III alpha-epsilon chimera
  4gx9		Crystal structure of a DNA polymerase III alpha-epsilon chimera
  4gyf		Crystal structure of histidinol phosphate phosphatase (HISK) from Lactococcus lactis subsp. lactis Il1403 complexed with ZN, L-histidinol and phosphate
  4iqj		Structure of PolIIIalpha-Tauc-DNA complex suggests an atomic model of the replisome
  4jom		Structure of E. coli Pol III 3mPHP mutant
  5fku		5FKU
  5fkv		5FKV
  5fkw		5FKW

• Links (links to other resources describing this domain)

• INTERPRO	IPR003141

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