Functions of WW domains in the nucleus.
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.
Sudol
M
M
Department of Medicine, Mount Sinai Medical Center, New York, NY 10029, USA. marius.sudol@mssm.edu
Sliwa
K
K
Russo
T
T
D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism; D002453:Cell Cycle; D006801:Humans; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism; D009687:Nuclear Proteins / Q000737:chemistry* / Q000378:metabolism*; D019696:Peptidylprolyl Isomerase / Q000737:chemistry / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012319:RNA Polymerase II / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic; D015003:Yeasts / Q000201:enzymology / Q000378:metabolism
C091042:APBB1 protein, human; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D012319:RNA Polymerase II; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase