Summary: WW domain
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WW domain Edit Wikipedia article
The WW domain, (also known as the rsp5-domain or WWP repeating motif) is a modular protein domain that mediates specific interactions with protein ligands. This domain is found in a number of unrelated signaling and structural proteins and may be repeated up to four times in some proteins. Apart from binding preferentially to proteins that are proline-rich, with particular proline-motifs, [AP]-P-P-[AP]-Y, some WW domains bind to phosphoserine- phosphothreonine-containing motifs.
Structure and ligands
The WW domain is one of the smallest protein modules, composed of only 40 amino acids, which mediates specific protein-protein interactions with short proline-rich or proline-containing motifs. Named after the presence of two conserved tryptophans (W), which are spaced 20-22 amino acids apart within the sequence, the WW domain folds into a meandering triple-stranded beta sheet. The identification of the WW domain was facilitated by the analysis of two splice isoforms of YAP gene product, named YAP1-1 and YAP1-2, which differed by the presence of an extra 38 amino acids. These extra amino acids are encoded by a spliced-in exon and represent the second WW domain in YAP1-2 isoform.
The first structure of the WW domain was determined in solution by NMR approach. It represented the WW domain of human YAP in complex with peptide ligand containing Proline-Proline-x–Tyrosine (PPxY where x = any amino acid) consensus motif. Recently, the YAP WW domain structure in complex with SMAD-derived, PPxY motif-containing peptide was further refined. Apart from the PPxY motif, certain WW domains recognize LPxY motif (where L is Leucine), and several WW domains bind to phospho-Serine-Proline (p-SP) or phospho-Threonine-Proline (p-TP) motifs in a phospho-dependent manner. Structures of these WW domain complexes confirmed molecular details of phosphorylation-regulated interactions. There are also WW domains that interact with polyprolines that are flanked by arginine residues or interrupted by leucine residues, but they do not contain aromatic amino acids.
The WW domain is known to mediate regulatory protein complexes in various signaling networks, including the Hippo signaling pathway. The importance of WW domain-mediated complexes in signaling was underscored by the characterization of genetic syndromes that are caused by loss-of-function point mutations in the WW domain or its cognate ligand. These syndromes are Golabi-Ito-Hall syndrome of intellectual disability caused by missense mutation in a WW domain and Liddle syndrome of hypertension caused by point mutations within PPxY motif.
A large variety of proteins containing the WW domain are known. These include; dystrophin, a multidomain cytoskeletal protein; utrophin, a dystrophin-like protein; vertebrate YAP protein, substrate of LATS1 and LATS2 serine-theronine kinases of the Hippo tumor suppressor pathway; Mus musculus (Mouse) NEDD4, involved in the embryonic development and differentiation of the central nervous system; Saccharomyces cerevisiae (Baker's yeast) RSP5, similar to NEDD4 in its molecular organization; Rattus norvegicus (Rat) FE65, a transcription-factor activator expressed preferentially in brain; Nicotiana tabacum (Common tobacco) DB10 protein, amongst others.
In 2004, the first comprehensive protein-peptide interaction map for a human modular domain was reported using individually expressed WW domains and genome predicted, PPxY-containing synthetic peptides. At present in the human proteome, 98 WW domains and more than 2000 PPxY-containing peptides, have been identified from sequence analysis of the genome.
YAP is a WW domain-containing protein that functions as a potent oncogene. Its WW domains must be intact for YAP to act as a transcriptional co-activator that induces expression of proliferative genes. Recent study has shown that endohedral metallofullerenol, a compound that was originally developed as a contrasting agent for MRI (magnetic resonance imaging), has antineoplastic properties. Via molecular dynamic simulations, the ability of this compound to outcompete proline-rich peptides and bind effectively to the WW domain of YAP was documented. Endotheral metallofullerenol may represent a lead compound for the development of therapies for cancer patients who harbor amplified or overexpressed YAP.
In the study of protein folding
Because of its small size and well-defined structure, the WW domain became a favorite subject of protein folding studies. Among these studies, the work of Rama Ranganathan  and David E. Shaw are notable. Ranganathan’s team has shown that a simple statistical energy function, which identifies co-evolution between amino acid residues within the WW domain, is necessary and sufficient to specify sequence that folds into native structure. Using such an algorithm, he and his team synthesized libraries of artificial WW domains that functioned in a very similar manner to their natural counterparts, recognizing class-specific proline-rich ligand peptides, The Shaw laboratory developed a specialized machine that allowed elucidation of the atomic level behavior of the WW domain on a biologically relevant time scale. He and his team employed equilibrium simulations of a WW domain and identified seven unfolding and eight folding events that follow the same folding route.
- doi:10.1016/S0092-8674(00)80273-1. PMID 9200606.; Ranganathan R, Lu KP, Hunter T, Noel JP (June 1997). "Structural and functional analysis of the mitotic rotamase Pin1 suggests substrate recognition is phosphorylation dependent". Cell 89 (6): 875–86.
- Bork P, Sudol M (December 1994). "The WW domain: a signalling site in dystrophin?". Trends Biochem. Sci. 19 (12): 531–3. doi:10.1016/0968-0004(94)90053-1. PMID 7846762.
- Hofmann K, Bucher P (January 1995). "The rsp5-domain is shared by proteins of diverse functions". FEBS Lett. 358 (2): 153–7. doi:10.1016/0014-5793(94)01415-W. PMID 7828727.
- André B, Springael JY (December 1994). "WWP, a new amino acid motif present in single or multiple copies in various proteins including dystrophin and the SH3-binding Yes-associated protein YAP65". Biochem. Biophys. Res. Commun. 205 (2): 1201–5. doi:10.1006/bbrc.1994.2793. PMID 7802651.
- Sudol M, Chen HI, Bougeret C, Einbond A, Bork P (August 1995). "Characterization of a novel protein-binding module--the WW domain". FEBS Lett. 369 (1): 67–71. doi:10.1016/0014-5793(95)00550-S. PMID 7641887.
- Chen HI, Sudol M (August 1995). "The WW domain of Yes-associated protein binds a proline-rich ligand that differs from the consensus established for Src homology 3-binding modules". Proc. Natl. Acad. Sci. U.S.A. 92 (17): 7819–23. Bibcode:1995PNAS...92.7819C. doi:10.1073/pnas.92.17.7819. PMC 41237. PMID 7644498.
- Macias MJ, Hyvönen M, Baraldi E, Schultz J, Sudol M, Saraste M, Oschkinat H (August 1996). "Structure of the WW domain of a kinase-associated protein complexed with a proline-rich peptide". Nature 382 (6592): 646–9. Bibcode:1996Natur.382..646M. doi:10.1038/382646a0. PMID 8757138.
- Sudol M, Bork P, Einbond A, Kastury K, Druck T, Negrini M, Huebner K, Lehman D (June 1995). "Characterization of the mammalian YAP (Yes-associated protein) gene and its role in defining a novel protein module, the WW domain". J. Biol. Chem. 270 (24): 14733–41. doi:10.1074/jbc.270.24.14733. PMID 7782338.
- Aragón E, Goerner N, Xi Q, Gomes T, Gao S, Massagué J, Macias MJ (October 2012). "Structural basis for the versatile interactions of Smad7 with regulator WW domains in TGF-β Pathways". Structure 20 (10): 1726–36. doi:10.1016/j.str.2012.07.014. PMC 3472128. PMID 22921829.
- Bruce MC, Kanelis V, Fouladkou F, Debonneville A, Staub O, Rotin D (October 2008). "Regulation of Nedd4-2 self-ubiquitination and stability by a PY motif located within its HECT-domain". Biochem. J. 415 (1): 155–63. doi:10.1042/BJ20071708. PMID 18498246.
- Lu PJ, Zhou XZ, Shen M, Lu KP (February 1999). "Function of WW domains as phosphoserine- or phosphothreonine-binding modules". Science 283 (5406): 1325–8. Bibcode:1999Sci...283.1325L. doi:10.1126/science.283.5406.1325. PMID 10037602.
- Verdecia MA, Bowman ME, Lu KP, Hunter T, Noel JP (August 2000). "Structural basis for phosphoserine-proline recognition by group IV WW domains". Nat. Struct. Biol. 7 (8): 639–43. doi:10.1038/77929. PMID 10932246.
- Bedford MT, Sarbassova D, Xu J, Leder P, Yaffe MB (April 2000). "A novel pro-Arg motif recognized by WW domains". J. Biol. Chem. 275 (14): 10359–69. doi:10.1074/jbc.275.14.10359. PMID 10744724.
- Ermekova KS, Zambrano N, Linn H, Minopoli G, Gertler F, Russo T, Sudol M (December 1997). "The WW domain of neural protein FE65 interacts with proline-rich motifs in Mena, the mammalian homolog of Drosophila enabled". J. Biol. Chem. 272 (52): 32869–77. doi:10.1074/jbc.272.52.32869. PMID 9407065.
- Sudol M, Harvey KF (November 2010). "Modularity in the Hippo signaling pathway". Trends Biochem. Sci. 35 (11): 627–33. doi:10.1016/j.tibs.2010.05.010. PMID 20598891.
- Lubs H, Abidi FE, Echeverri R, Holloway L, Meindl A, Stevenson RE, Schwartz CE (June 2006). "Golabi-Ito-Hall syndrome results from a missense mutation in the WW domain of the PQBP1 gene". J. Med. Genet. 43 (6): e30. doi:10.1136/jmg.2005.037556. PMC 2564547. PMID 16740914.
- Tapia VE, Nicolaescu E, McDonald CB, Musi V, Oka T, Inayoshi Y, Satteson AC, Mazack V, Humbert J, Gaffney CJ, Beullens M, Schwartz CE, Landgraf C, Volkmer R, Pastore A, Farooq A, Bollen M, Sudol M (June 2010). "Y65C missense mutation in the WW domain of the Golabi-Ito-Hall syndrome protein PQBP1 affects its binding activity and deregulates pre-mRNA splicing". J. Biol. Chem. 285 (25): 19391–401. doi:10.1074/jbc.M109.084525. PMC 2885219. PMID 20410308.
- Schild L, Lu Y, Gautschi I, Schneeberger E, Lifton RP, Rossier BC (May 1996). "Identification of a PY motif in the epithelial Na channel subunits as a target sequence for mutations causing channel activation found in Liddle syndrome". EMBO J. 15 (10): 2381–7. PMC 450168. PMID 8665845.
- Staub O, Gautschi I, Ishikawa T, Breitschopf K, Ciechanover A, Schild L, Rotin D (November 1997). "Regulation of stability and function of the epithelial Na+ channel (ENaC) by ubiquitination". EMBO J. 16 (21): 6325–36. doi:10.1093/emboj/16.21.6325. PMC 1170239. PMID 9351815.
- Hu H, Columbus J, Zhang Y, Wu D, Lian L, Yang S, Goodwin J, Luczak C, Carter M, Chen L, James M, Davis R, Sudol M, Rodwell J, Herrero JJ (March 2004). "A map of WW domain family interactions". Proteomics 4 (3): 643–55. doi:10.1002/pmic.200300632. PMID 14997488.
- Sudol M, McDonald CB, Farooq A (August 2012). "Molecular insights into the WW domain of the Golabi-Ito-Hall syndrome protein PQBP1". FEBS Lett. 586 (17): 2795–9. doi:10.1016/j.febslet.2012.03.041. PMC 3413755. PMID 22710169.
- Huang J, Wu S, Barrera J, Matthews K, Pan D (August 2005). "The Hippo signaling pathway coordinately regulates cell proliferation and apoptosis by inactivating Yorkie, the Drosophila Homolog of YAP". Cell 122 (3): 421–34. doi:10.1016/j.cell.2005.06.007. PMID 16096061.
- Zhao B, Kim J, Ye X, Lai ZC, Guan KL (February 2009). "Both TEAD-binding and WW domains are required for the growth stimulation and oncogenic transformation activity of yes-associated protein". Cancer Res. 69 (3): 1089–98. doi:10.1158/0008-5472.CAN-08-2997. PMID 19141641.
- Kang SG, Zhou G, Yang P, Liu Y, Sun B, Huynh T, Meng H, Zhao L, Xing G, Chen C, Zhao Y, Zhou R (September 2012). "Molecular mechanism of pancreatic tumor metastasis inhibition by Gd@C82(OH)22 and its implication for de novo design of nanomedicine". Proc. Natl. Acad. Sci. U.S.A. 109 (38): 15431–6. Bibcode:2012PNAS..10915431K. doi:10.1073/pnas.1204600109. PMC 3458392. PMID 22949663.
- Kang SG, Huynh T, Zhou R (2012). "Non-destructive inhibition of metallofullerenol Gd@C(82)(OH)(22) on WW domain: implication on signal transduction pathway". Sci Rep 2: 957. Bibcode:2012NatSR...2E.957K. doi:10.1038/srep00957. PMC 3518810. PMID 23233876.
- Sudol M, Shields DC, Farooq A (September 2012). "Structures of YAP protein domains reveal promising targets for development of new cancer drugs". Semin. Cell Dev. Biol. 23 (7): 827–33. doi:10.1016/j.semcdb.2012.05.002. PMC 3427467. PMID 22609812.
- Fuller AA, Du D, Liu F, Davoren JE, Bhabha G, Kroon G, Case DA, Dyson HJ, Powers ET, Wipf P, Gruebele M, Kelly JW (July 2009). "Evaluating beta-turn mimics as beta-sheet folding nucleators". Proc. Natl. Acad. Sci. U.S.A. 106 (27): 11067–72. Bibcode:2009PNAS..10611067F. doi:10.1073/pnas.0813012106. PMC 2708776. PMID 19541614.
- Jager M, Deechongkit S, Koepf EK, Nguyen H, Gao J, Powers ET, Gruebele M, Kelly JW (2008). "Understanding the mechanism of beta-sheet folding from a chemical and biological perspective". Biopolymers 90 (6): 751–8. doi:10.1002/bip.21101. PMID 18844292.
- Jäger M, Zhang Y, Bieschke J, Nguyen H, Dendle M, Bowman ME, Noel JP, Gruebele M, Kelly JW (July 2006). "Structure-function-folding relationship in a WW domain". Proc. Natl. Acad. Sci. U.S.A. 103 (28): 10648–53. Bibcode:2006PNAS..10310648J. doi:10.1073/pnas.0600511103. PMC 1502286. PMID 16807295.
- Russ WP, Lowery DM, Mishra P, Yaffe MB, Ranganathan R (September 2005). "Natural-like function in artificial WW domains". Nature 437 (7058): 579–83. Bibcode:2005Natur.437..579R. doi:10.1038/nature03990. PMID 16177795.
- Socolich M, Lockless SW, Russ WP, Lee H, Gardner KH, Ranganathan R (September 2005). "Evolutionary information for specifying a protein fold". Nature 437 (7058): 512–8. Bibcode:2005Natur.437..512S. doi:10.1038/nature03991. PMID 16177782.
- Piana S, Sarkar K, Lindorff-Larsen K, Guo M, Gruebele M, Shaw DE (January 2011). "Computational design and experimental testing of the fastest-folding β-sheet protein". J. Mol. Biol. 405 (1): 43–8. doi:10.1016/j.jmb.2010.10.023. PMID 20974152.
- Shaw DE, Maragakis P, Lindorff-Larsen K, Piana S, Dror RO, Eastwood MP, Bank JA, Jumper JM, Salmon JK, Shan Y, Wriggers W (October 2010). "Atomic-level characterization of the structural dynamics of proteins". Science 330 (6002): 341–6. Bibcode:2010Sci...330..341S. doi:10.1126/science.1187409. PMID 20947758.
- Eukaryotic Linear Motif resource motif class LIG_WW_1
- Eukaryotic Linear Motif resource motif class LIG_WW_2
- Eukaryotic Linear Motif resource motif class LIG_WW_3
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.
WW domain Provide feedback
The WW domain is a protein module with two highly conserved tryptophans that binds proline-rich peptide motifs in vitro.
Macias MJ, Hyvonen M, Baraldi E, Schultz J, Sudol M, Saraste M, Oschkinat H; , Nature 1996;382:646-649.: Structure of the WW domain of a kinase-associated protein complexed with a proline-rich peptide. PUBMED:8757138 EPMC:8757138
Shcherbik N, Kumar S, Haines DS; , J Cell Sci 2002;115:1041-1048.: Substrate proteolysis is inhibited by dominant-negative Nedd4 and Rsp5 mutants harboring alterations in WW domain 1. PUBMED:11870222 EPMC:11870222
Ermekova KS, Zambrano N, Linn H, Minopoli G, Gertler F, Russo T, Sudol M; , J Biol Chem 1998;272:32869-32877.: The WW domain of neural protein FE65 interacts with proline-rich motifs in Mena, the mammalian homolog of Drosophila enabled. PUBMED:9407065 EPMC:9407065
Chen HI, Sudol M; , Proc Natl Acad Sci U S A 1995;92:7819-7823.: The WW domain of Yes-associated protein binds a proline-rich ligand that differs from the consensus established for Src homology 3-binding modules. PUBMED:7644498 EPMC:7644498
Internal database links
|SCOOP:||MbtH Hydrolase_2 Glyco_hydro_101|
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR001202
Synonym(s): Rsp5 or WWP domain
The WW domain is a short conserved region in a number of unrelated proteins, which folds as a stable, triple stranded beta-sheet. This short domain of approximately 40 amino acids, may be repeated up to four times in some proteins [PUBMED:7846762, PUBMED:7802651, PUBMED:7828727, PUBMED:7641887]. The name WW or WWP derives from the presence of two signature tryptophan residues that are spaced 20-23 amino acids apart and are present in most WW domains known to date, as well as that of a conserved Pro. The WW domain binds to proteins with particular proline-motifs, [AP]-P-P-[AP]-Y, and/or phosphoserine- phosphothreonine-containing motifs [PUBMED:7644498, PUBMED:11911877]. It is frequently associated with other domains typical for proteins in signal transduction processes.
A large variety of proteins containing the WW domain are known. These include; dystrophin, a multidomain cytoskeletal protein; utrophin, a dystrophin-like protein of unknown function; vertebrate YAP protein, substrate of an unknown serine kinase; Mus musculus (Mouse) NEDD-4, involved in the embryonic development and differentiation of the central nervous system; Saccharomyces cerevisiae (Baker's yeast) RSP5, similar to NEDD-4 in its molecular organisation; Rattus norvegicus (Rat) FE65, a transcription-factor activator expressed preferentially in liver; Nicotiana tabacum (Common tobacco) DB10 protein, amongst others.
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Molecular function||protein binding (GO:0005515)|
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:
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We make a range of alignments for each Pfam-A family:
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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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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.
|Number in seed:||514|
|Number in full:||9912|
|Average length of the domain:||29.90 aa|
|Average identity of full alignment:||36 %|
|Average coverage of the sequence by the domain:||6.14 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 11927849 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||23|
|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.
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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.
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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.
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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.
Unfortunately we have found that there are problems viewing the interactive tree when the it becomes larger than a certain limit. Furthermore, we have found that Internet Explorer can become unresponsive when viewing some trees, regardless of their size. We therefore show a text representation of the species tree when the size is above a certain limit or if you are using Internet Explorer to view the site.
If you are using IE you can still load the interactive tree by clicking the "Generate interactive tree" button, but please be aware of the potential problems that the interactive species tree can cause.
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.
You can use the tree controls to manipulate how the interactive tree is displayed:
- show/hide the summary boxes
- highlight species that are represented in the seed alignment
- expand/collapse the tree or expand it to a given depth
- select a sub-tree or a set of species within the tree and view them graphically or as an alignment
- save a plain text representation of the tree
Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.
There are 6 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 WW domain has been found. There are 154 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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