Class of 2006
adibello@jhu.edu

Research
Cell signaling via post-translational modification by ubiquitin is an important mechanism in eukaryotic cellular regulation. The ubiquitination of a target protein results in the covalent attachment of ubiquitin to the target protein via an isopeptide bond between a lysine residue in the target protein and the carboxyl group of the C-terminal glycine of ubiquitin. Ubiquitin, itself, contains several lysine residues that can also be ubiquitinated, thereby creating poly-ubiquitin chains. The best-characterized ubiquitin lysine residues involved in poly-ubiquitination are Lys 48 and Lys 63 (K48 and K63). It is the distinct type of linkage in these poly-ubiquitin chains (K48, K63 or otherwise) that determines the cellular signal or the fate of the target protein. K48 linked poly-ubiquitinated substrates are recognized by members of the ubiquitin-proteasome pathway (UPP) and are ultimately targeted for degradation by the proteasome. K63 linkages are involved in other cellular functions such as DNA repair, the NF-kB pathway and other signal transduction pathways. De-ubiquitinating enzymes catalyze the cleavage of the isopeptide bond between ubiquitin and the ubiquitinated protein. De-ubiquitinating enzymes function in a variety of cellular pathways, many cleaving poly-ubiquitinated substrates with varying degrees of poly-ubiquitin chain linkage specificity. By degrading K48 linked poly-ubiquitin chains, de-ubiquitinating enzymes can serve to prevent degradation of a target protein. De-ubiquitinating enzymes also maintain sufficient levels of free mono-ubiquitin that are needed for the ubiquitination of other targets. It has also been suggested that de-ubiquitinating enzymes play an editing and proofreading role by removing ubiquitins from proteins that have been inappropriately targeted to the proteasome or other ubiquitin designated fates.

Ataxin-3 is a human de-ubiquitinating enzyme first identified for its role as the disease protein in the polyglutamine expansion neurodegenerative disease, Machado-Joseph Disease / Spinocerebellar Ataxia type 3. Although there has been much work to investigate the role of ataxin-3 in the context of disease, little is known about its normal cellular and biochemical function. In their cellular signaling role and as cellular regulators, de-ubiquitinating enzymes must be able recognize the structural nature of the isopeptide linkage and the distinct lysine linkage topologies of poly-ubiquitin chains. Little is known about how de-ubiquitinating enzymes and other proteins that recognize poly-ubiquitin signals are able to achieve linkage specificity. I am investigating the structural determinants of poly-ubiquitin linkage specificity and function of human ataxin-3 through kinetic assays and x-ray crystallography. More broadly, I am interested in how de-ubiquitinating enzymes and other poly-ubiquitin interacting proteins are able achieve linkage specific recognition and function in one of the most important and evolutionary conserved systems in biology.

Publications