Ubiquitin: a multifunctional regulatory protein associated with the cytoskeleton.

The discovery that ubiquitin is associated with the neurofibrillary tangles of Alzheimer's disease and inclusion bodies of other neurodegenerative disorders raises the possibility that ubiquitin is playing a role in the pathology. Ubiquitin is a small, highly conserved protein that is found both free and covalently attached to other proteins in all eukaryotic cells. Ubiquitin is conjugated with some proteins that are rapidly degraded and with a select set of regulatory proteins that are relatively stable, implying that ubiquitin is multifunctional. We have produced monoclonal antibodies to ubiquitin and identified the epitopes. Different monoclonal antibodies recognize different ubiquitin-protein conjugates; this could be due to different conformational states of ubiquitin or to steric interference by the conjugated protein. These observations suggest that ubiquitin is structurally and therefore functionally different in different contexts. Ubiquitin is localized in several compartments in cells and this may also affect function. We discovered that it is a normal component of the microtubule network and have identified ubiquitinated proteins in bovine brain that appear associated with microtubules. We discovered that ubiquitin has intrinsic proteolytic activity and proposed that ubiquitin-protein conjugates could function as ad hoc proteases. This proteolytic activity offers a heuristic basis from which to explore ubiquitin's cellular functions. The association of ubiquitin with the cytoskeletal networks suggests that proteolytic processing is a function of these structures. Disruption of these structures in neurodegenerative disorders, improper localization of ubiquitinated components or appearance of abnormal conjugates could lead to altered proteolytic processing pathways and contribute to the pathology of these diseases.