Summary: WH1 domain
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WH1 domain Edit Wikipedia article
WH1 domain is an evolutionary conserved protein domain. Therefore, it has an important function. WH1 domains are found on WASP proteins, which are often involved in actin polymerization. Hence, WH1 is important for all cellular processes involving actin, this includes cell motility, cell trafficking, cell division and cytokinesis, cell signalling, and the establishment and maintenance of cell junctions and cell shape.
The WASP protein family control actin polymerization by activating the Arp2/3 complex. WASP is defective in Wiskott-Aldrich syndrome (WAS) whereby in most patient cases, the majority of point mutations occur within the N-terminal WH1 domain. The metabotropic glutamate receptors mGluR1alpha and mGluR5 bind a protein called homer, which is a WH1 domain homologue.
A subset of WH1 domains has been termed the EVH1 domain and appear to bind a polyproline motif. The EVH1 (WH1, RanBP1-WASP) domain is found in multi-domain proteins implicated in a diverse range of signalling, nuclear transport and cytoskeletal events. This domain of around 115 amino acids is present in species ranging from yeast to mammals. Many EVH1-containing proteins associate with actin-based structures and play a role in cytoskeletal organisation. EVH1 domains recognise and bind the proline-rich motif FPPPP with low-affinity, further interactions then form between flanking residues.
WASP family proteins contain an EVH1 (WH1) in their N-terminals which bind proline-rich sequences in the WASP interacting protein. Proteins of the RanBP1 family contain a WH1 domain in their N-terminal region, which seems to bind a different sequence motif present in the C-terminal part of RanGTP protein.
Tertiary structure of the WH1 domain of the Mena protein revealed structure similarities with the pleckstrin homology (PH) domain. The overall fold consists of a compact parallel beta-sandwich, closed along one edge by a long alpha-helix. A highly conserved cluster of three surface-exposed aromatic side-chains forms the recognition site for the molecules target ligands.
Human genes encoding proteins containing the WH1 domain include:
- Symons M, Derry JM, Karlak B, Jiang S, Lemahieu V, Mccormick F, Francke U, Abo A (March 1996). "Wiskott-Aldrich syndrome protein, a novel effector for the GTPase CDC42Hs, is implicated in actin polymerization". Cell 84 (5): 723–34. doi:10.1016/S0092-8674(00)81050-8. PMID 8625410.
- Veltman DM, Insall RH (2010). "WASP family proteins: their evolution and its physiological implications.". Mol Biol Cell 21 (16): 2880–93. doi:10.1091/mbc.E10-04-0372. PMC 2921111. PMID 20573979.
- Ponting CP, Phillips C (1997). "Identification of homer as a homologue of the Wiskott-Aldrich syndrome protein suggests a receptor-binding function for WH1 domains". J. Mol. Med. 75 (11-12): 769–71. doi:10.1007/s001090050166. PMID 9428607.
- Niebuhr K, Ebel F, Frank R, Reinhard M, Domann E, Carl UD, Walter U, Gertler FB, Wehland J, Chakraborty T (September 1997). "A novel proline-rich motif present in ActA of Listeria monocytogenes and cytoskeletal proteins is the ligand for the EVH1 domain, a protein module present in the Ena/VASP family". EMBO J. 16 (17): 5433–44. doi:10.1093/emboj/16.17.5433. PMC 1170174. PMID 9312002.
- Ball LJ, Jarchau T, Oschkinat H, Walter U (February 2002). "EVH1 domains: structure, function and interactions". FEBS Lett. 513 (1): 45–52. doi:10.1016/S0014-5793(01)03291-4. PMID 11911879.
- Callebaut I, Cossart P, Dehoux P (December 1998). "EVH1/WH1 domains of VASP and WASP proteins belong to a large family including Ran-binding domains of the RanBP1 family". FEBS Lett. 441 (2): 181–5. doi:10.1016/S0014-5793(98)01541-5. PMID 9883880.
- Beddow AL, Richards SA, Orem NR, Macara IG (April 1995). "The Ran/TC4 GTPase-binding domain: identification by expression cloning and characterization of a conserved sequence motif". Proc. Natl. Acad. Sci. U.S.A. 92 (8): 3328–32. doi:10.1073/pnas.92.8.3328. PMC 42159. PMID 7724562.
- Prehoda KE, Lee DJ, Lim WA (May 1999). "Structure of the enabled/VASP homology 1 domain-peptide complex: a key component in the spatial control of actin assembly". Cell 97 (4): 471–80. doi:10.1016/S0092-8674(00)80757-6. PMID 10338211.
- Eukaryotic Linear Motif resource motif class LIG_EVH1_1
- Eukaryotic Linear Motif resource motif class LIG_EVH1_2
- Eukaryotic Linear Motif resource motif class LIG_WH1
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WASp Homology domain 1 (WH1) domain. WASP is the protein that is defective in Wiskott-Aldrich syndrome (WAS). The majority of point mutations occur within the amino- terminal WH1 domain. The metabotropic glutamate receptors mGluR1alpha and mGluR5 bind a protein called homer, which is a WH1 domain homologue . A subset of WH1 domains has been termed a "EVH1" domain  and appear to bind a polyproline motif.
Symons M, Derry JM, Karlak B, Jiang S, Lemahieu V, Mccormick F, Francke U, Abo A; , Cell 1996;84:723-734.: Wiskott-Aldrich syndrome protein, a novel effector for the GTPase CDC42Hs, is implicated in actin polymerization. PUBMED:8625410 EPMC:8625410
Ponting CP, Phillips C; , J Mol Med. 1997;75:769-771.: Identification of homer as a homologue of the Wiskott-Aldrich syndrome protein suggests a receptor-binding function for WH1 domains PUBMED:9428607 EPMC:9428607
Niebuhr K, Ebel F, Frank R, Reinhard M, Domann E, Carl UD, Walter U, Gertler FB, Wehland J, Chakraborty T; , EMBO J 1997;16:5433-5444.: A novel proline-rich motif present in ActA of Listeria monocytogenes and cytoskeletal proteins is the ligand for the EVH1 domain, a protein module present in the Enas/VASP family. PUBMED:9312002 EPMC:9312002
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR000697
The EVH1 (WH1, RanBP1-WASP) domain is found in multi-domain proteins implicated in a diverse range of signalling, nuclear transport and cytoskeletal events. This domain of around 115 amino acids is present in species ranging from yeast to mammals. Many EVH1-containing proteins associate with actin-based structures and play a role in cytoskeletal organisation. EVH1 domains recognise and bind the proline-rich motif FPPPP with low-affinity, further interactions then form between flanking residues [PUBMED:11911879, PUBMED:9312002].
WASP family proteins contain a EVH1 (WH1) in their N-terminals which bind proline-rich sequences in the WASP interacting protein. Proteins of the RanBP1 family contain a WH1 domain in their N-terminal region, which seems to bind a different sequence motif present in the C-terminal part of RanGTP protein [PUBMED:9883880,PUBMED:7724562].
Tertiary structure of the WH1 domain of the Mena protein revealed structure similarities with the pleckstrin homology (PH) domain. The overall fold consists of a compact parallel beta-sandwich, closed along one edge by a long alpha-helix. A highly conserved cluster of three surface-exposed aromatic side-chains forms the recognition site for the molecules target ligands. [PUBMED:10338211].
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
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Members of this clan share a PH-like fold. Many families in this clan bind to short peptide motifs in proteins and are involved in signalling.
The clan contains the following 38 members:bPH_1 bPH_2 bPH_3 bPH_4 bPH_5 bPH_6 DCP1 DUF1448 DUF1681 FERM_C GRAM ICAP-1_inte_bdg IQ_SEC7_PH IRS Mcp5_PH PH PH_10 PH_11 PH_12 PH_13 PH_2 PH_3 PH_4 PH_5 PH_6 PH_8 PH_9 PH_BEACH PH_TFIIH PID PID_2 PTB Ran_BP1 Rtt106 SSrecog Voldacs Vps36_ESCRT-II WH1
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:
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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.
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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Curation and family details
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|Seed source:||Alignment kindly provided by SMART|
|Number in seed:||8|
|Number in full:||1769|
|Average length of the domain:||104.40 aa|
|Average identity of full alignment:||26 %|
|Average coverage of the sequence by the domain:||24.17 %|
|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:||19|
|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.
In order to reduce the complexity of the representation, we reduce the number of taxonomic levels that we show. We consider only the following eight major taxonomic levels:
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Segments of the tree are coloured approximately according to their superkingdom. For example, archeal branches are coloured with shades of orange, eukaryotes in shades of purple, etc. The colour assignments are shown under the sunburst controls. Where space allows, the name of the taxonomic level will be written on the arc itself.
As you move your mouse across the sunburst, the current node will be highlighted. In the top section of the controls panel we show a summary of the lineage of the currently highlighed node. If you pause over an arc, a tooltip will be shown, giving the name of the taxonomic level in the title and a summary of the number of sequences and species below that node in the tree.
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There are some situations that the sunburst tree cannot easily handle and for which we have work-arounds in place.
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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.
Too many species/sequences
For large species trees, you may see blank regions in the outer layers of the sunburst. These occur when there are large numbers of arcs to be drawn in a small space. If an arc is less than approximately one pixel wide, it will not be drawn and the space will be left blank. You may still be able to get some information about the species in that region by moving your mouse across the area, but since each arc will be very small, it will be difficult to accurately locate a particular species.
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 WH1 domain has been found. There are 27 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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