Functions of WW domains in the nucleus

The WW domain is a protein module found in a wide range of signaling protei ns. It is one of the smallest protein modules that folds as a monomer witho ut disulfide bridges or cofactors. WW domains bind proteins containing shor t linear peptide motifs that are proline-rich or contain at least one proli ne. Although the WW domain was initially considered a 'cytoplasmic module', the proteins containing WW domains have also been localized in the cell nu cleus. Moreover, these proteins have been documented to participate in co-a ctivation of transcription and modulation of RNA polymerase II activity. Th e carboxy-terminal domain (CTD) of RNA polymerase II acts as an assembly pl atform for distinct WW domain-containing proteins that affect the function of the RNA polymerase II. The formation of complexes between CTD and WW dom ain-containing proteins is regulated by phosphorylation of the CTD. Since t he CTD sequence is highly repetitive and a target of several posttranslatio nal modifications and conformational changes, it presents a unique structur e capable of enormous molecular diversity. The WW domain has been implicate d in several human diseases including Alzheimer's disease. The WW domain-co ntaining iso-prolyl isomerase named Pin1, a protein known to be essential f or cell cycle progression, was shown to be active in restoration of the mic rotubule-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 in teracts directly with Tau protein. In addition, the WW domain-containing ad apter 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 illumin ate numerous signaling pathways which control certain aspects of transcript ion and cell cycle. (C) 2001 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved.