Functions of WW domains in the nucleus

Abstract

The WW domain is a protein module found in a wide range of signaling proteins. It is one of the smallest protein modules that folds as a monomer without disulfide bridges or cofactors. WW domains bind proteins containing short linear peptide motifs that are proline‐rich or contain at least one proline. Although the WW domain was initially considered a ‘cytoplasmic module’, the proteins containing WW domains have also been localized in the cell nucleus. Moreover, these proteins have been documented to participate in co‐activation of transcription and modulation of RNA polymerase II activity. The carboxy‐terminal domain (CTD) of RNA polymerase II acts as an assembly platform for distinct WW domain‐containing proteins that affect the function of the RNA polymerase II. The formation of complexes between CTD and WW domain‐containing proteins is regulated by phosphorylation of the CTD. Since the CTD sequence is highly repetitive and a target of several post‐translational modifications and conformational changes, it presents a unique structure capable of enormous molecular diversity. The WW domain has been implicated in several human diseases including Alzheimer's disease. The WW domain‐containing iso‐prolyl isomerase named Pin1, a protein known to be essential for cell cycle progression, was shown to be active in restoration of the microtubule‐binding activity of Tau, a protein of neurofibrillar tangles found in the brains of Alzheimer's patients. It is the WW domain of Pin1 that interacts directly with Tau protein. In addition, the WW domain‐containing adapter protein FE65 was shown to regulate processing of Alzheimer's amyloid precursor protein. It is expected that by understanding the details of the WW domain‐mediated protein–protein interactions, we will be able to illuminate numerous signaling pathways which control certain aspects of transcription and cell cycle.