WW domain

The WW domain,[2] (also known as the rsp5-domain[3] or WWP repeating motif[4]) 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.[2][3][4][5] 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.[6]

WW domain
Structure of the human mitotic rotamase Pin1.[1]
Identifiers
SymbolWW
PfamPF00397
InterProIPR001202
PROSITEPDOC50020
SCOPe1pin / SUPFAM
CDDcd00201

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.[6] Named after the presence of two conserved tryptophans (W), which are spaced 20-22 amino acids apart within the sequence,[2] the WW domain folds into a meandering triple-stranded beta sheet.[7] 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.[2][8]

The first structure of the WW domain was determined in solution by NMR approach.[7] 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.[6][7] Recently, the YAP WW domain structure in complex with SMAD-derived, PPxY motif-containing peptide was further refined.[9] Apart from the PPxY motif, certain WW domains recognize LPxY motif (where L is Leucine),[10] and several WW domains bind to phospho-Serine-Proline (p-SP) or phospho-Threonine-Proline (p-TP) motifs in a phospho-dependent manner.[11] Structures of these WW domain complexes confirmed molecular details of phosphorylation-regulated interactions.[1][12] 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.[13][14]

Signaling function

The WW domain is known to mediate regulatory protein complexes in various signaling networks, including the Hippo signaling pathway.[15] 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[16][17] and Liddle syndrome of hypertension caused by point mutations within PPxY motif.[18][19]

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-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.[20]

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.[21] At present in the human proteome, 98 WW domains[22] and more than 2000 PPxY-containing peptides,[17] have been identified from sequence analysis of the genome.

Inhibitor

YAP is a WW domain-containing protein that functions as a potent oncogene.[2][23] Its WW domains must be intact for YAP to act as a transcriptional co-activator that induces expression of proliferative genes.[24] 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.[25] 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.[26] Endotheral metallofullerenol may represent a lead compound for the development of therapies for cancer patients who harbor amplified or overexpressed YAP.[26][27]

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.[28][29][30] Among these studies, the work of Rama Ranganathan [31][32] and David E. Shaw are notable.[33][34] 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.[32] 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,[31] 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.[33] 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.[34]

Being a relatively short, 30 to 35 amino acids long, WW domain is amenable to chemical synthesis. It is cooperatively folded and can host chemically introduced non-canonical amino acids. Based on these properties, WW domain has been shown to be a versatile platform for the chemical interrogation of intramolecular interactions and conformational propensities in folded proteins.[35]

gollark: One problem is that the sheer amount of options for various things makes it really hard to decide anything.
gollark: Yes, I got that much.
gollark: *remains confused*.
gollark: Well, that definitely helped!
gollark: Spoky.

References
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  2. Bork P, Sudol M (December 1994). "The WW domain: a signalling site in dystrophin?". Trends in Biochemical Sciences. 19 (12): 531–3. doi:10.1016/0968-0004(94)90053-1. PMID 7846762.
  3. Hofmann K, Bucher P (January 1995). "The rsp5-domain is shared by proteins of diverse functions". FEBS Letters. 358 (2): 153–7. doi:10.1016/0014-5793(94)01415-W. PMID 7828727.
  4. 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". Biochemical and Biophysical Research Communications. 205 (2): 1201–5. doi:10.1006/bbrc.1994.2793. PMID 7802651.
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  14. 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". The Journal of Biological Chemistry. 272 (52): 32869–77. doi:10.1074/jbc.272.52.32869. PMID 9407065.
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  20. InterPro: IPR001202
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