WW domain

The WW domain

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

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

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.^{[28][29][30][31][32][33]} Among these studies, the work of Rama Ranganathan^[34][35] and David E. Shaw are also notable.^[36][37] 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.^[35] 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,^[34] 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.^[36] He and his team employed equilibrium simulations of a WW domain and identified seven unfolding and eight folding events.^[37]

Being 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.^[38]

References