Centre for Research in Biomolecular Interactions presents Prof. Gary S. Shaw, Department of Biochemistry, University of Western Ontario

Talk Title: "A Structural View of Ubiquitination in Parkinson’s Disease"

Abstract:

Ubiquitination is the major protein degradation pathway in cells that involves the transfer of ubiquitin between a series of enzymes until it covalently labels a lysine residue of a substrate protein. During this process ubiquitin is passed on through a series of enzymes – an activating enzyme E1, an E2 conjugating enzyme and finally an E3 ligase enzyme that orchestrates the substrate labelling. This cascade constitutes a large array of covalent and non-covalent interactions between the key proteins involved. Not surprisingly, several diseases are caused by the breakdown of these interactions leading to compromises in the removal of unwanted proteins.

The central protein responsible for early-onset Parkinson’s disease is parkin, a 465-residue E3 ligase that ubiquitinates specific mitochondrial proteins in response to oxidative stress. It is well established that missense mutations in the parkin gene lead to its dysfunction and the development of Parkinson’s disease. Parkin is a multi-domain enzyme comprising an N-terminal 76-residue “ubiquitin-like” (Ubl) domain and a C-terminal catalytic region. Using a combination of x-ray crystallography, NMR spectroscopy and isothermal titration calorimetry we have investigated the structures and functions of individual domains, the near full-length enzyme and parkin in complex with phosphorylated ubiquitin, a known activator of the enzyme. In this work the structural changes that allow parkin to move from an inactive (autoinhibited) state to its activated form, and how Parkinson’s disease mutations alter this, will be described.

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Refreshments will be served.