The award of the Nobel Prize for Chemistry to Avram Hershko, Aaron Ciechanover and Irwin Rose in 2004 for the discovery of “ubiquitin-dependent protein degradation” was an appropriate accolade for a major discovery in biochemistry in the second half of the 20th century. It is now apparent that protein ubiquitylation/deubiquitylation ranks with protein phosphorylation/dephosphorylation as an important post-translation modification of proteins in the regulation of cell physiology.
Proteins can be phosphorylated on serine, threonine, tyrosine and histidine residues, whereas protein ubiquitylation occurs predominately on lysine residues. The information richness of protein ubiquitylation is extended considerably by the fact that proteins can be monoubiquitylated, polyubiquitylated (chains of ubiquitin attached to a single lysine residue) or multiubiquitylated (one or more ubiquitins attached to different lysine residues). The utility of ubiquitin as a post-translational signal is extended further by the fact that ubiquitin has seven lysine residues, any of which can be used in the formation of ubiquitin chains that are attached to proteins. For example, ubiquitin chains formed through lysine 48 linkages are primarily recognised by the 26S proteasome for degradation of the polyubiquitylated target protein, while ubiquitin chains formed through lysine 63 linkages are recognised by ubiquitin-binding proteins involved in intracellular signalling pathways. Recent evidence also points to the existence of ‘forked’ polyubiquitin chains with mixed lysine linkages. >> Read more
Dr Rob Layfield has worked on the basic biology of the small modifier protein ubiquitin, and in particular human disorders of ubiquitin-mediated processes, since graduating from the University of Nottingham in 1990. After working as a post-doc with John Mayer, from 1997-2000 he held a Research into Ageing Fellowship and in 2000 was awarded a Wellcome Trust Research Career Development Fellowship. As part of the latter he worked with Maria Spillantini at the University of Cambidge. In 2000 he made the first mechanistic connections between dysfunction of the ubiquitin-proteasome system and Alzheimer's disease. Current work includes structural and functional studies of p62/SQSTM1, a protein which is mutated in the skeletal disorder Paget's disease of bone. Significantly, recent research has shown that Paget's disease (with SQSTM1 mutations) represent the archetypal example of human condition associated with loss of function mutations in a ubiquitin-binding protein.
Professor Mayer has worked on intracellular proteolysis for 40 years and on the ubiquitin proteasome system (UPS) since 1987. Early protein microinjection studies identified a "protein sequestration site associated with the microtubule organising centre for protein degradation by autophagy" later better named by Ron Kopito (Stanford) as the "aggresome". This work lead to studies on the UPS and chronic neurodegenerative disease because all the diseases are characterised by inclusions made of protein aggregates. The Nottingham group showed that inclusions in Parkinson's disease and amyotrophic lateral sclerosis contain ubiquitylated proteins. Additionally, these immunohistochemical investigations led to the discovery of cortical Lewy bodies by ubiquitin immunohistochemistry and the identification of Dementia with Lewy bodies, which is the second most common cause of cognitive decline in the elderly after Alzheimer's disease. This work has now culminated in a recent publication describing the generation by the Cre-recombinase/loxP genetic approach of the first mouse model of dementia with Lewy bodies and a new model of Parkinson's disease by the regional ablation of a 26S proteasome regulatory ATPase gene. An alternative approach, originally based on yeast two-hybrid screens, searching for interaction partners with another proteasomal ATPase, led to the discovery with Prof. Jun Fujita (Kyoto University) of gankyrin, the first liver oncoprotein. Gankyrin is overexpressed in hepatocellular carcinoma. Gankyrin regulates the activity of the retinoblastoma protein, p53 and NFKB to oppose apoptosis and encourage the development of hepatocelluar carcinoma.
