Summary: PX domain
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PX domain Edit Wikipedia article
PX domain of NADH oxidase (p40phox), lipid-bound
This domain was first found in P40phox and p47phox domains of NADPH oxidase (phox stands for phagocytic oxidase). It was also identified in many other proteins involved in membrane trafficking, including nexins, Phospholipase D, and phosphoinositide-3-kinases.
The PX domain is structurally conserved in eukaryotes, although amino acid sequences show little similarity. PX domains interact primarily with PtdIns(3)P lipids. However some of them bind to phosphatidic acid, PtdIns(3,4)P2, PtdIns(3,5)P2, PtdIns(4,5)P2, and PtdIns(3,4,5)P3. The PX-domain can also interact with other domains and proteins.
Human proteins containing this domain
Sorting nexins contain this domain. Other examples include:
- KIF16B (SNX23)
- NCF1; NCF1C; NCF4; NISCH
- PIK3C2A; PIK3C2B; PIK3C2G; PLD1; PLD2; PXK
- SGK3; SH3PXD2A; SNAG1
- Ponting CP (November 1996). "Novel domains in NADPH oxidase subunits, sorting nexins, and PtdIns 3-kinases: binding partners of SH3 domains?". Protein Sci. 5 (11): 2353–7. doi:10.1002/pro.5560051122. PMC 2143296. PMID 8931154.
- Wishart MJ, Taylor GS, Dixon JE (June 2001). "Phoxy lipids: revealing PX domains as phosphoinositide binding modules". Cell 105 (7): 817–20. doi:10.1016/S0092-8674(01)00414-7. PMID 11439176.
- Hiroaki H, Ago T, Ito T, Sumimoto H, Kohda D (June 2001). "Solution structure of the PX domain, a target of the SH3 domain". Nat. Struct. Biol. 8 (6): 526–30. doi:10.1038/88591. PMID 11373621.
- Karathanassis D, Stahelin RV, Bravo J, Perisic O, Pacold CM, Cho W, Williams RL (October 2002). "Binding of the PX domain of p47phox to phosphatidylinositol 3,4-bisphosphate and phosphatidic acid is masked by an intramolecular interaction". EMBO J. 21 (19): 5057–68. doi:10.1093/emboj/cdf519. PMC 129041. PMID 12356722.
- Ago T, Kuribayashi F, Hiroaki H, Takeya R, Ito T, Kohda D, Sumimoto H (April 2003). "Phosphorylation of p47phox directs phox homology domain from SH3 domain toward phosphoinositides, leading to phagocyte NADPH oxidase activation". Proc. Natl. Acad. Sci. U.S.A. 100 (8): 4474–9. doi:10.1073/pnas.0735712100. PMC 153580. PMID 12672956.
This is the Wikipedia entry entitled "Sorting nexin". More...
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Sorting nexin Edit Wikipedia article
Structure of the PX domain from p40(phox) bound to phosphatidylinositol 3-phosphate.
|Sorting nexin, N-terminal domain|
|Vps5 C terminal like (BAR domain)|
|Sorting nexin, C terminal domain|
Sorting nexins are a large group of proteins that are localized in the cytoplasm and have the potential for membrane association either through their lipid-binding PX domain (a phospholipid-binding motif) or through protein-protein interactions with membrane-associated protein complexes Some members of this family have been shown to facilitate protein sorting.
In humans, sorting nexins are transcribed from the following genes:
|SNX1, SNX2||Sorting_nexin_N||–||PX||–||BAR (Vps5)|
|SNX4, SNX7, SNX8, SNX30||–||–||PX||–||BAR (Vsp5)|
|SNX5, SNX6, SNX32||–||–||PX||–||BAR|
|SNX9, SNX18, SNX33||SH3||–||PX||–||BAR (BAR_3_WASP_bdg)|
|SNX13, SNX14, SNX19, SNX25||PXA||RGS||PX||–||Nexin_C|
|SNX3, SNX10, SNX11, SNX12, SNX16, SNX20, SNX21, SNX22, SNX24, SNX29||–||–||PX||–||–|
Sorting nexins either consist solely of a PX domain (e.g. SNX3) or have a modular structure made up of the PX and additional domains.
A subgroup of sorting nexins (comprising, in humans, SNX1, SNX2, SNX4, SNX5, SNX6, SNX7, SNX8, SNX9, SNX18, SNX30, SNX32 and SNX33) possess a BAR domain at their C-terminus. (The BAR domain of SNXs 1, 2, 4, 7, 8 and 30 is classified by pfam as 'Vps5 C terminal like'.)
An example of a sorting nexin domain structure can be seen here for SNX1:
- Bravo J, Karathanassis D, Pacold CM, et al. (October 2001). "The crystal structure of the PX domain from p40(phox) bound to phosphatidylinositol 3-phosphate". Mol. Cell 8 (4): 829–39. doi:10.1016/S1097-2765(01)00372-0. PMID 11684018.
- Dixon JE, Worby CA (2002). "Sorting out the cellular functions of sorting nexins". Nat. Rev. Mol. Cell Biol. 3 (12): 919–931. doi:10.1038/nrm974. PMID 12461558.
- Worby CA, Dixon JE (2002). "Sorting out the cellular functions of sorting nexins". Nat. Rev. Mol. Cell Biol. 3 (12): 919–31. doi:10.1038/nrm974. PMID 12461558.
- Frost A, Unger VM, De Camilli P (April 2009). "The BAR domain superfamily: membrane-molding macromolecules". Cell 137 (2): 191–196. doi:10.1016/j.cell.2009.04.010. PMID 19379681.
- BAR_3_WASP_bdg: WASP-binding domain of Sorting nexin protein, Pfam PF10456
- PXA: PXA domain, Pfam PF02194
- MIT: MIT (microtubule interacting and transport) domain, Pfam PF04212
- RA: Ras association (RalGDS/AF-6) domain, Pfam PF00788
- FERM_M: FERM central domain, Pfam PF00373
- SMAD_FHA: SMAD/FHA domain, IPR008984
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PX domain Provide feedback
PX domains bind to phosphoinositides.
Karathanassis D, Stahelin RV, Bravo J, Perisic O, Pacold CM, Cho W, Williams RL; , EMBO J 2002;21:5057-5068.: Binding of the PX domain of p47(phox) to phosphatidylinositol 3,4-bisphosphate and phosphatidic acid is masked by an intramolecular interaction. PUBMED:12356722 EPMC:12356722
Ago T, Kuribayashi F, Hiroaki H, Takeya R, Ito T, Kohda D, Sumimoto H; , Proc Natl Acad Sci U S A 2003;100:4474-4479.: Phosphorylation of p47phox directs phox homology domain from SH3 domain toward phosphoinositides, leading to phagocyte NADPH oxidase activation. PUBMED:12672956 EPMC:12672956
Internal database links
|SCOOP:||PseudoU_synth_2 Mmp37 GerPC DUF4364|
External database links
This tab holds annotation information from the InterPro database.
InterPro entry 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]. 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 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 recent multiple alignment of representative PX domain sequences can be found in [PUBMED:9687503], although showing relatively little sequence conservation, 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].
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Molecular function||phosphatidylinositol binding (GO:0035091)|
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
The graphic that is shown by default represents the longest sequence with a given architecture. Each row contains the following information:
- the number of sequences which exhibit this architecture
a textual description of the architecture, e.g. Gla, EGF x 2, Trypsin.
This example describes an architecture with one
Gladomain, followed by two consecutive
EGFdomains, and finally a single
- a link to the page in the Pfam site showing information about the sequence that the graphic describes
- the UniProt description of the protein sequence
- the number of residues in the sequence
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Note that you can see the family page for a particular domain by clicking on the graphic. You can also choose to see all sequences which have a given architecture by clicking on the Show link in each row.
Finally, because some families can be found in a very large number of architectures, we load only the first fifty architectures by default. If you want to see more architectures, click the button at the bottom of the page to load the next set.
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- alignment generated by searching the NCBI sequence database using the family HMM
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1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
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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.
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|Seed source:||Alignment kindly provided by SMART & iterated|
|Number in seed:||67|
|Number in full:||13807|
|Average length of the domain:||115.00 aa|
|Average identity of full alignment:||21 %|
|Average coverage of the sequence by the domain:||20.12 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 80369284 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||20|
|Download:||download the raw HMM for this family|
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This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the More....
This chart is a modified "sunburst" visualisation of the species tree for this family. It shows each node in the tree as a separate arc, arranged radially with the superkingdoms at the centre and the species arrayed around the outermost ring.
How the sunburst is generated
The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, its distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.
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Some species in the taxonomic tree may not have one or more of the main eight levels that we display. For example, Bos taurus is not assigned an order in the NCBI taxonomic tree. In such cases we mark the omitted level with, for example, "No order", in both the tooltip and the lineage summary.
Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".
Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.
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The tree shows the occurrence of this domain across different species. More...
We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.
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For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.
Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.
We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
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There are 3 interactions for this family. More...
We determine these interactions using iPfam, which considers the interactions between residues in three-dimensional protein structures and maps those interactions back to Pfam families. You can find more information about the iPfam algorithm in the journal article that accompanies the website.
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 PX domain has been found. There are 73 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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