WWDomain with 2 conserved Trp (W) residues
|SMART accession number:||SM00456|
|Description:||Also known as the WWP or rsp5 domain. Binds proline-rich polypeptides.|
|Interpro abstract (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.
|GO function:||protein binding (GO:0005515)|
Click on the following links for more information.
- Evolution (species in which this domain is found)
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This tree shows only several representative species. The complete taxonomic breakdown of all proteins with WW domain is also avaliable.
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Go to specific node: Anopheles gambiae, Arabidopsis thaliana, Caenorhabditis elegans, Drosophila melanogaster, Homo sapiens, Mus musculus, Rattus norvegicus, Saccharomyces cerevisiae, Takifugu rubripes
- Cellular role (predicted cellular role)
Cellular role: interaction, signalling
Binding / catalysis: protein-binding, polyproline-binding
- Literature (relevant references for this domain)
Primary literature is listed below; Automatically-derived, secondary literature is also avaliable.
- Bedford MT, Reed R, Leder P
- WW domain-mediated interactions reveal a spliceosome-associated protein that binds a third class of proline-rich motif: the proline glycine and methionine-rich motif.
- Proc Natl Acad Sci U S A. 1998; 95: 10602-7
- Display abstract
Pre-mRNA splicing requires the bridging of the 5' and 3' ends of the intron. In yeast, this bridging involves interactions between the WW domains in the splicing factor PRP40 and a proline-rich domain in the branchpoint binding protein, BBP. Using a proline-rich domain derived from formin (a product of the murine limb deformity locus), we have identified a family of murine formin binding proteins (FBP's), each of which contains one or more of a special class of tyrosine-rich WW domains. Two of these WW domains, in the proteins FBP11 and FBP21, are strikingly similar to those found in the yeast splicing factor PRP40. We show that FBP21 is present in highly purified spliceosomal complex A, is associated with U2 snRNPs, and colocalizes with splicing factors in nuclear speckle domains. Moreover, FBP21 interacts directly with the U1 snRNP protein U1C, the core snRNP proteins SmB and SmB', and the branchpoint binding protein SF1/mBBP. Thus, FBP21 may play a role in cross-intron bridging of U1 and U2 snRNPs in the mammalian A complex.
- Neele DM, Kaptein A, Huisman H, deWit EC, Princen HM
- No effect of fibrates on synthesis of apolipoprotein(a) in primary cultures of cynomolgus monkey and human hepatocytes: apolipoprotein A-I synthesis increased.
- Biochem Biophys Res Commun. 1998; 244: 374-8
- Display abstract
Fibrates have been shown to decrease plasma levels of triglyceride-rich lipoproteins and LDL and to increase HDL. Data on the effect of fibrates on lipoprotein(a) levels in man are not consistent. Because lp(a) levels in vivo are mainly regulated at synthesis level, we studied the effect of fibrates on the synthesis of apolipoprotein(a) (apo(a)) in primary cultures of cynomolgus monkey and human hepatocytes. Furthermore, we assessed the effect of fibrates on apolipoprotein A-I (apo A-I) synthesis and investigated whether different fibrates have different effects on the apo(a) and apo A-I synthesis. The addition of gemfibrozil to cultures of monkey and human hepatocytes had no effect on apo(a) synthesis, but resulted in a dose- and time-dependent increase of apo A-I synthesis and mRNA. In simian hepatocytes maximal stimulation was 2.5-fold after incubation for 72 h with 1.0 mM gemfibrozil, whereas apo A-I synthesis was induced 1.8- and 2.0-fold by using 0.1 mM and 0.3 mM, respectively. Similar results were obtained by using human hepatocytes; apo(a) synthesis remained unchanged, while apo A-I secretion was 2.0-fold increased at 1 mM gemfibrozil. Other fibrates like bezafibrate, clofibrate and clofibric acid did not change apo(a) synthesis either. In contrast, they enhanced the synthesis of apo A-I (1.5-, 1.8- and 1.8-fold, respectively), although less potently than gemfibrozil. We conclude that fibrates have no effect on apolipoprotein(a) synthesis in monkey and human hepatocytes and that these drugs induce apo A-I synthesis.
- Rotin D
- WW (WWP) domains: from structure to function.
- Curr Top Microbiol Immunol. 1998; 228: 115-33
- DiFiore PP, Pelicci PG, Sorkin A
- EH: a novel protein-protein interaction domain potentially involved in intracellular sorting.
- Trends Biochem Sci. 1997; 22: 411-3
- Ermekova KS et al.
- The WW domain of neural protein FE65 interacts with proline-rich motifs in Mena, the mammalian homolog of Drosophila enabled.
- J Biol Chem. 1997; 272: 32869-77
- Display abstract
The neural protein FE65 contains two types of protein-protein interaction modules: one WW binding domain and two phosphotyrosine binding domains. The carboxyl-terminal phosphotyrosine binding domain of FE65 interacts in vivo with the beta-amyloid precursor protein, which is implicated in Alzheimer disease. To understand the function of this adapter protein, we identified binding partners for the FE65 WW domain. Proline-rich sequences sharing a proline-proline-leucine-proline core motif were recovered by screening expression libraries for ligands of the FE65 WW domain. Five proteins of molecular masses 60, 75, 80, 140, and 200 kDa could be purified from mouse brain lysates by affinity to the FE65 WW domain. We identified two of these five proteins as the 80- and 140-kDa isoforms encoded by Mena, the mammalian homolog of the Drosophila Enabled gene. Using the SPOTs technique of peptide synthesis, we identified the sequences in Mena that interact with the FE65 WW domain and found that they contain the signature proline-proline-leucine-proline motif. Finally, we demonstrated that Mena binds to FE65 in vivo by coimmunoprecipitation assay from COS cell extracts. The specificity of the Mena-FE65 WW domain association was confirmed by competition assays. Further characterization of the FE65-Mena complex may identify a physiological role for these proteins in beta-amyloid precursor protein biogenesis and may help in understanding the mechanism of molecular changes that underlie Alzheimer disease.
- Gavva NR, Gavva R, Ermekova K, Sudol M, Shen CJ
- Interaction of WW domains with hematopoietic transcription factor p45/NF-E2 and RNA polymerase II.
- J Biol Chem. 1997; 272: 24105-8
- Display abstract
NF-E2 is an erythroid-specific transcription factor required for expression of several erythroid-specific genes. By Far-Western blotting and yeast two-hybrid assay, we demonstrate that p45, the large subunit of NF-E2, is capable of binding to a specific set of WW domain-containing proteins, including the ubiquitin ligase hRPF1. This binding is mediated through the interaction between the WW domains and a PY motif located within the amino-terminal region of p45. Interestingly, the carboxyl-terminal domain of mammalian RNA polymerase II binds a similar set of WW domains to which p45 interacts with. We discuss the data in terms of possible new pathways through which the processes of transcriptional regulation by NF-E2 could be regulated in erythroid and megakaryote cells.
- Macias MJ et al.
- Structure of the WW domain of a kinase-associated protein complexed with a proline-rich peptide.
- Nature. 1996; 382: 646-9
- Display abstract
The WW domain is a new protein module with two highly conserved tryptophans that binds proline-rich peptide motifs in vitro. It is present in a number of signalling and regulatory proteins, often in several copies. Here we investigate the solution structure of the WW domain of human YAP65 (for Yes kinase-associated protein) in complex with proline-rich peptides containing the core motif PPxY. The structure of the domain with the bound peptide GTPPPPYTVG is a slightly curved, three-stranded, antiparallel beta-sheet. Two prolines pack against the first tryptophan, forming a hydrophobic buckle on the convex side of the sheet. The concave side has three exposed hydrophobic residues (tyrosine, tryptophan and leucine) which form the binding site for the ligand. A non-conserved isoleucine in the amino-terminal flanking region covers a hydrophobic patch and stabilizes the WW domain of human YAP65 in vitro. The structure of the WW domain differs from that of the SH3 domain and reveals a new design for a protein module that uses stacked aromatic surface residues to arrange a binding site for proline-rich peptides.
- Ponting CP, Blake DJ, Davies KE, Kendrick-Jones J, Winder SJ
- ZZ and TAZ: new putative zinc fingers in dystrophin and other proteins.
- Trends Biochem Sci. 1996; 21: 11-13
- Hofmann K, Bucher P
- The rsp5-domain is shared by proteins of diverse functions.
- FEBS Lett. 1995; 358: 153-7
- Display abstract
A novel, unusually small, and highly conserved domain of modular intracellular proteins is described. The domain was first recognized as three repeats in the yeast rsp5 gene product and named thereafter. The rsp5 protein is thought to interact with nuclear proteins but also contains a C2 domain typical for cytoplasmic proteins. Further analyses revealed several additional occurrences of this domain in diverse protein classes, including cytoplasmic signal transduction proteins, gene products interacting with the transcription machinery, structural proteins like dystrophin, and a putative RNA helicase.
- Sudol M et al.
- Characterization of the mammalian YAP (Yes-associated protein) gene and its role in defining a novel protein module, the WW domain.
- J Biol Chem. 1995; 270: 14733-41
- Display abstract
We report cDNA cloning and characterization of the human and mouse orthologs of the chicken YAP (Yes-associated protein) gene which encodes a novel protein that binds to the SH3 (Src homology 3) domain of the Yes proto-oncogene product. Sequence comparison between mouse, human, and chicken YAP proteins showed an inserted sequence in the mouse YAP that represented an imperfect repeat of an upstream sequence. Further analysis of this sequence revealed a putative protein module that is found in various structural, regulatory, and signaling molecules in yeast, nematode, and mammals including human dystrophin. Because one of the prominent features of this sequence motif is two tryptophans (W), we named it the WW domain (Bork, P., and Sudol, M. (1994) Trends Biochem. Sci. 19, 531-533). Since its delineation, more proteins have been shown to contain this domain, and we report here on the widespread distribution of the WW module and present a discussion of its possible function. We have also shown that the human YAP gene is well conserved among higher eukaryotes, but it may not be conserved in yeast. Its expression at the RNA level in adult human tissues is nearly ubiquitous, being relatively high in placenta, prostate, ovary, and testis, but is not detectable in peripheral blood leukocytes. Using fluorescence in situ hybridization on human metaphase chromosomes and by analyzing rodent-human hybrids by Southern blot hybridization and polymerase chain reaction amplification, we mapped the human YAP gene to chromosome band 11q13, a region to which the multiple endocrine neoplasia type 1 gene has been mapped.
- Andre B, Springael JY
- 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. 1994; 205: 1201-5
- Display abstract
A new repeating amino acid motif, which we called WWP, was found in several proteins of yeast, nematod or vertebrate origin. Among these are dystrophin, the product of the Duchenne muscular dystrophy locus, a protein (YAP65) which associates in vitro with the Src homology domain 3 (SH3) of the Yes proto-oncogene product, and a human putative GTPase-activating protein. As is the case for proteins which contain the SH2, SH3 and PH domains, at least some of the WWP-containing proteins appear to be signaling or cytoskeletal proteins, associated with plasma or organellar membranes, and specific protein-protein contacts are likely to be crucial to their function.
- Bork P, Sudol M
- The WW domain: a signalling site in dystrophin?
- Trends Biochem Sci. 1994; 19: 531-3
- Kobe B, Deisenhofer J
- The leucine-rich repeat: a versatile binding motif.
- Trends Biochem Sci. 1994; 19: 415-21
- Display abstract
Leucine-rich repeats are short sequence motifs present in a number of proteins with diverse functions and cellular locations. All proteins containing these repeats are thought to be involved in protein-protein interactions. The crystal structure of ribonuclease inhibitor protein has revealed that leucine-rich repeats correspond to beta-alpha structural units. These units are arranged so that they form a parallel beta-sheet with one surface exposed to solvent, so that the protein acquires an unusual, nonglobular shape. These two features may be responsible for the protein-binding functions of proteins containing leucine-rich repeats.
- Maclennan AJ, Shaw G
- A yeast SH2 domain.
- Trends Biochem Sci. 1993; 18: 464-5
- 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 23.53 map04120 Ubiquitin mediated proteolysis 21.57 map05050 Dentatorubropallidoluysian atrophy (DRPLA) 15.69 map04530 Tight junction 10.78 map04350 TGF-beta signaling pathway 5.88 map05010 Alzheimer's disease 3.92 map04810 Regulation of actin cytoskeleton 1.96 map00260 Glycine, serine and threonine metabolism 1.96 map00625 Tetrachloroethene degradation 1.96 map00650 Butanoate metabolism 1.96 map00591 Linoleic acid metabolism 1.96 map00052 Galactose metabolism 1.96 map00120 Bile acid biosynthesis 1.96 map00380 Tryptophan metabolism 1.96 map00363 Bisphenol A degradation 1.96 map00051 Fructose and mannose metabolism 0.98 map00230 Purine metabolism
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 WW domain which could be assigned to a KEGG orthologous group, and not all proteins containing WW 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 WW domains in PDB
PDB code Main view Title 1e0l Fbp28ww domain from mus musculus 1e0m Prototype ww domain 1eg3 Structure of a dystrophin ww domain fragment in complex with a beta-dystroglycan peptide 1eg4 Structure of a dystrophin ww domain fragment in complex with a beta-dystroglycan peptide 1f8a Structural basis for the phosphoserine-proline recognition by group iv ww domains 1i5h Solution structure of the rnedd4 wwiii domain-renac bp2 peptide complex 1i6c Solution structure of pin1 ww domain 1i8g Solution structure of pin1 ww domain complexed with cdc25 phosphothreonine peptide 1i8h Solution structure of pin1 ww domain complexed with human tau phosphothreonine peptide 1jmq Yap65 (l30k mutant) ww domain in complex with gtppppytvg peptide 1k5r Yap65 ww domain s24-amino-ethylsulfanyl-acetic acid mutant 1k9q Yap65 ww domain complexed to n-(n-octyl)-gpppy-nh2 1k9r Yap65 ww domain complexed to acetyl-plppy 1nmv Solution structure of human pin1 1o6w Solution structure of the prp40 ww domain pair of the yeast splicing factor prp40 1pin Pin1 peptidyl-prolyl cis-trans isomerase from homo sapiens 1tk7 Nmr structure of ww domains (ww3-4) from suppressor of deltex 1wmv Solution structure of the second ww domain of wwox 1wr3 Solution structure of the first ww domain of nedd4-2 1wr4 Solution structure of the second ww domain of nedd4-2 1wr7 Solution structure of the third ww domain of nedd4-2 1yiu Itch e3 ubiquitin ligase ww3 domain 1ymz Cc45, an artificial ww domain designed using statistical coupling analysis 1yw5 Peptidyl-prolyl isomerase ess1 from candida albicans 1ywi Structure of the fbp11ww1 domain complexed to the peptide apptppplpp 1ywj Structure of the fbp11ww1 domain 1zcn Human pin1 ng mutant 1zr7 Solution structure of the first ww domain of fbp11 2djy Solution structure of smurf2 ww3 domain-smad7 py peptide complex 2dk1 Solution structure of ww domain in ww domain binding protein 4 (wbp-4) 2dk7 Solution structure of ww domain in transcription elongation regulator 1 2dmv Solution structure of the second ww domain of itchy homolog e3 ubiquitin protein ligase (itch) 2dwv Solution structure of the second ww domain from mouse salvador homolog 1 protein (mww45) 2dyf Solution structure of the first ww domain of fbp11 / hypa (fbp11 ww1) complexed with a pl (pplp) motif peptide ligand 2e45 Solution structure of fe65 ww domain 2ez5 Solution structure of the dnedd4 ww3* domain- comm lpsy peptide complex 2f21 Human pin1 fip mutant 2ho2 Structure of human fe65-ww domain in complex with hmena peptide. 2idh Crystal structure of human fe65 ww domain 2itk Human pin1 bound to d-peptide 2jmf Solution structure of the su(dx) ww4- notch py peptide complex 2jo9 Mouse itch 3rd ww domain complex with the epstein-barr virus latent membrane protein 2a derived peptide eeppppyed 2joc Mouse itch 3rd domain phosphorylated in t30 2jup Fbp28ww2 domain in complex with the pplipppp peptide 2jv4 Structure characterisation of pina ww domain and comparison with other group iv ww domains, pin1 and ess1 2jx8 Solution structure of hpcif1 ww domain 2jxw Solution structure of the tandem ww domains of fbp21 2kbu Nmr solution structure of pin1 ww domain mutant with beta turn mimic at position 12 2kcf The nmr solution structure of the isolated apo pin1 ww domain 2nnt General structural motifs of amyloid protofilaments 2oei Crystal structure of human fe65-ww domain in complex with human mena peptide 2op7 Ww4 2q5a Human pin1 bound to l-peptide 2rly Fbp28ww2 domain in complex with ptppplpp peptide 2rm0 Fbp28ww2 domain in complex with a ppplipppp peptide 2ysb Solution structure of the first ww domain from the mouse salvador homolog 1 protein (sav1) 2ysc Solution structure of the ww domain from the human amyloid beta a4 precursor protein-binding family b member 3, apbb3 2ysd Solution structure of the first ww domain from the human membrane-associated guanylate kinase, ww and pdz domain- containing protein 1. magi-1 2yse Solution structure of the second ww domain from the human membrane-associated guanylate kinase, ww and pdz domain- containing protein 1. magi-1 2ysf Solution structure of the fourth ww domain from the human e3 ubiquitin-protein ligase itchy homolog, itch 2ysg Solution structure of the ww domain from the human syntaxin- binding protein 4 2ysh Solution structure of the ww domain from the human growth- arrest-specific protein 7, gas-7 2ysi Solution structure of the first ww domain from the mouse transcription elongation regulator 1, transcription factor ca150 2zaj Solution structure of the short-isoform of the second ww domain from the human membrane-associated guanylate kinase, ww and pdz domain-containing protein 1 (magi-1) 2zqs Crystal structure of a mutant pin1 peptidyl-prolyl cis-trans isomerase 2zqt Crystal structure of a mutant pin1 peptidyl-prolyl cis-trans isomerase 2zqu Crystal structure of a mutant pin1 peptidyl-prolyl cis-trans isomerase 2zqv Crystal structure of a mutant pin1 peptidyl-prolyl cis-trans isomerase 2zr4 Crystal structure of a mutant pin1 peptidyl-prolyl cis-trans isomerase 2zr5 Crystal structure of a mutant pin1 peptidyl-prolyl cis-trans isomerase 2zr6 Crystal structure of a mutant pin1 peptidyl-prolyl cis-trans isomerase
- Links (links to other resources describing this domain)
PFAM WW_rsp5_WWP INTERPRO IPR001202 PROSITE WW_DOMAIN_2