Taxonomic distribution of proteins containing WW domains

The WW domain within your query sequence starts at position 493 and ends at position 525, and its E-value is 6.82e-11.

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.

Bedford MT, Reed R, Leder P
Proc Natl Acad Sci U S A. 1998; 95: 10602-7

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.

No effect of fibrates on synthesis of apolipoprotein(a) in primary cultures of cynomolgus monkey and human hepatocytes: apolipoprotein A-I synthesis increased.

Neele DM, Kaptein A, Huisman H, deWit EC, Princen HM
Biochem Biophys Res Commun. 1998; 244: 374-8

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.

WW (WWP) domains: from structure to function.

Rotin D
Curr Top Microbiol Immunol. 1998; 228: 115-33

EH: a novel protein-protein interaction domain potentially involved in intracellular sorting.

DiFiore PP, Pelicci PG, Sorkin A
Trends Biochem Sci. 1997; 22: 411-3

The WW domain of neural protein FE65 interacts with proline-rich motifs in Mena, the mammalian homolog of Drosophila enabled.

Ermekova KS, Zambrano N, Linn H, Minopoli G, Gertler F, Russo T, Sudol M
J Biol Chem. 1997; 272: 32869-77

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.

Interaction of WW domains with hematopoietic transcription factor p45/NF-E2 and RNA polymerase II.

Gavva NR, Gavva R, Ermekova K, Sudol M, Shen CJ
J Biol Chem. 1997; 272: 24105-8

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.

Structure of the WW domain of a kinase-associated protein complexed with a proline-rich peptide.

Macias MJ, Hyvonen M, Baraldi E, Schultz J, Sudol M, Saraste M, Oschkinat H
Nature. 1996; 382: 646-9

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.

ZZ and TAZ: new putative zinc fingers in dystrophin and other proteins.

Ponting CP, Blake DJ, Davies KE, Kendrick-Jones J, Winder SJ
Trends Biochem Sci. 1996; 21: 11-13

The rsp5-domain is shared by proteins of diverse functions.

Hofmann K, Bucher P
FEBS Lett. 1995; 358: 153-7

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.

Characterization of the mammalian YAP (Yes-associated protein) gene and its role in defining a novel protein module, the WW domain.

Sudol M, Bork P, Einbond A, Kastury K, Druck T, Negrini M, Huebner K, Lehman D
J Biol Chem. 1995; 270: 14733-41

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.

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.

Andre B, Springael JY
Biochem Biophys Res Commun. 1994; 205: 1201-5

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.

The WW domain: a signalling site in dystrophin?

Bork P, Sudol M
Trends Biochem Sci. 1994; 19: 531-3

The leucine-rich repeat: a versatile binding motif.

Kobe B, Deisenhofer J
Trends Biochem Sci. 1994; 19: 415-21

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.

A yeast SH2 domain.

Maclennan AJ, Shaw G
Trends Biochem Sci. 1993; 18: 464-5