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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PX PhoX homologous domain, present in p47phox and p40phox.

SMART accession number:	SM00312
Description:	Eukaryotic domain of unknown function present in phox proteins, PLD isoforms, a PI3K isoform.
Interpro abstract (IPR001683):	The PX (phox) domain [ (PUBMED:8931154) ] occurs in a variety of eukaryotic proteins and have been implicated in highly diverse functions such as cell signalling, vesicular trafficking, protein sorting and lipid modification [ (PUBMED:10782093) (PUBMED:11736640) (PUBMED:12461558) (PUBMED:16782399) ]. PX domains are important phosphoinositide-binding modules that have varying lipid-binding specificities [ (PUBMED:11884510) ]. The PX domain is approximately 120 residues long [ (PUBMED:11373621) ], and folds into a three-stranded beta-sheet followed by three -helices and a proline-rich region that immediately preceeds a membrane-interaction loop and spans approximately eight hydrophobic and polar residues. The PX domain of neutrophil cytosol factor 1 (p47phox) binds to the SH3 domain in the same protein [ (PUBMED:11373621) ]. Phosphorylation of p47(phox), a cytoplasmic activator of the microbicidal phagocyte oxidase (phox), elicits interaction of p47(phox) with phoinositides. The protein phosphorylation-driven conformational change of p47(phox) enables its PX domain to bind to phosphoinositides, the interaction of which plays a crucial role in recruitment of p47(phox) from the cytoplasm to membranes and subsequent activation of the phagocyte oxidase. The lipid-binding activity of this protein is normally suppressed by intramolecular interaction of the PX domain with the C-terminal Src homology 3 (SH3) domain [ (PUBMED:12356722) ]. The PX domain is conserved from yeast to human. A multiple alignment of representative PX domain sequences from eukaryotic proteins [ (PUBMED:9687503) ], shows relatively little sequence conservation, although their structure appears to be highly conserved. Although phosphatidylinositol-3-phosphate (PtdIns(3)P) is the primary target of PX domains, binding to phosphatidic acid, phosphatidylinositol-3,4-bisphosphate (PtdIns(3,4)P2), phosphatidylinositol-3,5-bisphosphate (PtdIns(3,5)P2), phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2), and phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3) has been reported as well. The PX-domain is also a protein-protein interaction domain [ (PUBMED:15263065) ].
GO function:	phosphatidylinositol binding (GO:0035091)
Family alignment:	View or CHROMA formatHMM/Web logoCLUSTALW formatMSF formatFASTA formatPIR format

There are 32485 PX domains in 32392 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 PX domain.

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

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

• Cellular role (predicted cellular role)

• Cellular role: signalling
  

• Literature (relevant references for this domain)

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

  • Vollert CS, Uetz P
  • The phox homology (PX) domain protein interaction network in yeast.
  • Mol Cell Proteomics. 2004; 3: 1053-64
  • Display abstract

  • The phox homology (PX) domain is a phosphoinositide-binding domain that is conserved from yeast to human. Here we show for the first time by genome-wide two-hybrid screens and in vitro binding assays that the PX domain is a bona fide protein interaction domain. The yeast PX domain-only proteins Grd19p (YOR357C) and Ypt35p (YHR105W), as well as the isolated PX domains from Mvp1p (YMR004W), Snx42p/Cvt20p/Atg20p (YDL113C), Vam7p (YGL212W), and Vps17p (YOR132W), yielded a total of 40 reproducible two-hybrid interactions. Thirty-five interactions were found for the full-length proteins of Bem1p (YBR200W), Snx42p, Snx4p/Cvt13p (YJL036W), Vam7p, Vps5p (YOR069W), and Vps17p, but these appear not to require the PX domain, because these interactions could not be reproduced with PX-only baits. Interactions of Grd19p, Vam7p, Vps5p, Vps17p, and Ypt35p with members of the Yip1p family of proteins were detected consistently and were verified by in vitro binding assays. The N-terminal cytoplasmic domain of Yip1p and Yif1p mediates these interactions with PX domains. A mutation in the lipid-binding pocket of Ypt35p that reduces lipid binding markedly does not affect these PX domain protein interactions, arguing that lipid binding uses a different interaction surface than protein binding.

  • Hiroaki H, Ago T, Ito T, Sumimoto H, Kohda D
  • Solution structure of the PX domain, a target of the SH3 domain.
  • Nat Struct Biol. 2001; 8: 526-30
  • Display abstract

  • The phox homology (PX) domain is a novel protein module containing aconserved proline-rich motif. We have shown that the PX domain isolatedfrom the human p47phox protein, a soluble subunit of phagocyte NADPHoxidase, binds specifically to the C-terminal SH3 domain derived from thesame protein. The solution structure of p47 PX has an alpha + betastructure with a novel folding motif topology and reveals that theproline-rich motif is presented on the molecular surface for easyrecognition by the SH3 domain. The proline-rich motif of p47 PX in thefree state adopts a distorted left-handed polyproline type II helixconformation.

  • Ponting CP
  • Novel domains in NADPH oxidase subunits, sorting nexins, and PtdIns 3-kinases: binding partners of SH3 domains?
  • Protein Sci. 1996; 5: 2353-7
  • Display abstract

  • Two SH3 domain-containing cytosolic components of the NADPH oxidase, p47phox and p40phox, are shown by analyses of their sequences to contain single copies of a novel class of domain, the PX (phox) domain. Homologous domains are demonstrated to be present in the Cpk class of phosphatidylinositol 3-kinase, S. cerevisiae Bem1p, and S. pombe Scd2, and a large family of human sorting nexin 1 (SNX1) homologues. The majority of these domains contains a polyproline motif, typical of SH3 domain-binding proteins. Two further findings are reported. A third NADPH oxidase subunit, p67phox, is shown to contain four tetratricopeptide repeats (TPRs) within its N-terminal RaclGTP-binding region, and a 28 residue motif in p40phox is demonstrated to be present in protein kinase C isoforms iota/lambda and zeta, and in three ZZ domain-containing proteins.

• 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 21.28 map00565 Ether lipid metabolism 21.28 map00564 Glycerophospholipid metabolism 21.28 map04912 GnRH signaling pathway 14.89 map04070 Phosphatidylinositol signaling system 14.89 map04670 Leukocyte transendothelial migration 6.38 map04130 SNARE interactions in vesicular transport 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 PX domain which could be assigned to a KEGG orthologous group, and not all proteins containing PX 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 PX domains in PDB

  PDB code	Main view	Title
  1gd5		SOLUTION STRUCTURE OF THE PX DOMAIN FROM HUMAN P47PHOX NADPH OXIDASE
  1h6h		Structure of the PX domain from p40phox bound to phosphatidylinositol 3-phosphate
  1kmd		SOLUTION STRUCTURE OF THE VAM7P PX DOMAIN
  1kq6		p47phox PX domain
  1o7k		human p47 PX domain complex with sulphates
  1ocs		Crystal structure of the yeast PX-doamin protein Grd19p (sorting nexin3) complexed to phosphatidylinosytol-3-phosphate.
  1ocu		Crystal structure of the yeast PX-domain protein Grd19p (sorting nexin 3) complexed to phosphatidylinosytol-3-phospahte.
  1xte		crystal structure of CISK-PX domain
  1xtn		crystal structure of CISK-PX domain with sulfates
  2ar5		Crystal structure of the mammalian C2alpha-PI3 Kinase PX-domain
  2csk		Solution structure of PX domain from human SNX12
  2czo		Solution Structure of the PX Domain of Bem1p
  2dyb		The crystal structure of human p40(phox)
  2ett		Solution Structure of Human Sorting Nexin 22 PX Domain
  2i4k		Solution Structure of the PX domain of Sorting Nexin 1
  2iwl		Structure of the PX Domain of Phosphoinositide 3-Kinase-C2alpha
  2l73		Structure of the NOXO1b PX domain
  2mxc		2MXC
  2rai		The PX-BAR membrane remodeling unit of Sorting Nexin 9
  2raj		SO4 bound PX-BAR membrane remodeling unit of Sorting Nexin 9
  2rak		PI(3)P bound PX-BAR membrane remodeling unit of Sorting Nexin 9
  2rea		Crystal structures of C2ALPHA-PI3 kinase PX-domain domain indicate conformational change associated with ligand binding.
  2red		Crystal structures of C2ALPHA-PI3 kinase PX-domain domain indicate conformational change associated with ligand binding.
  2v14		Kinesin 16B Phox-homology domain (KIF16B)
  2v6v		The structure of the Bem1p PX domain
  2wwe		Crystal structure of the phox homology domain of human phosphoinositide-3-kinase-C2-gamma
  2yps		Crystal structure of the PX domain of human sorting nexin 3
  3dyt		Crystal structure of Snx9PX-BAR (230-595), C2221
  3dyu		Crystal structure of Snx9PX-BAR (230-595), H32
  3fog		Crystal structure of the PX domain of sorting nexin-17 (SNX17)
  3hpb		Crystal structure of SNX5-PX domain in P212121 space group
  3hpc		Crystal structure of SNX5-PX domain in P21 space group
  3iq2		Human sorting nexin 7, phox homology (PX) domain
  3lui		Crystal structure of the SNX17 PX domain with bound sulphate
  3p0c		Nischarin PX-domain
  4akv		Crystal structure of human sorting nexin 33 (SNX33)
  4az9		Crystal structure of phox homology domain of human sorting nexin 24
  4bgj		Crystal structure of the phox-homology domain of human sorting nexin 14
  4has		Crystal structure of PX domain of human sorting nexin SNX27
  4ikb		Crystal structure of SNX11 PX domain
  4ikd		Crystal structure of SNX11 PX domain
  4on3		4ON3
  4oxw		4OXW
  4p2i		4P2I
  4p2j		4P2J
  4pqo		4PQO
  4pqp		4PQP
  4pzg		4PZG

• Links (links to other resources describing this domain)

• INTERPRO	IPR001683
  PFAM	PX

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