WW domain

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. == Signaling function ==

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. == Examples ==

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-threonine 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. == Inhibitor ==

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. Endohedral 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 was developed by the Gruebele and Kelly groups into a favorite subject of protein folding studies. == References ==