The WW domain: a protein module that binds proline-rich or proline-containing ligands

Definition of the WW domain and a brief summary of its function

(i) two conserved tryptophans (W) spaced 20-22 amino acids apart;

(ii) a block of two or three aromatic amino acids located centrally between the two signature tryptophans, and

(iii) a conserved proline located three amino acids carboxyterminal to the second conserved tryptophan.

The WW domain binds proline-rich or proline-containing ligands with dissociation constants in the range of 1 to 50 microM. Based on the ligand binding specificity, the WW domains can be divided into five groups (see *Classification of WW domains). One of the groups, Group IV represented by Pin1 WW domain has been shown to function as a phosphoserine- or phosphothreonine-binding module, adding to the relatively wide range of motifs recognized by WW domains. Three-dimensional structures of WW domains derived from different proteins have been solved by NMR spectroscopy or by X-ray crystallography (see Molmol figures of WW domains and complexes with 'PDB' coordinates). The WW domain seems to be evolutionary well conserved. It is present in plants, yeast, worm, fly, and vertebrates. The WW domain is an intracellular module because it occurs in cytoplasmic and nuclear proteins. The WW domain has become a subject of general interest because several signaling complexes that the domain mediates have been implicated in human diseases including Muscular Dystrophy, Alzheimer's Disease, Huntington Disease, Liddle Syndrome of hypertension and recently in Cancer.