Structural and functional studies of ubiquitin kinases

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Living organisms and their constituent cells must respond to environmental cues to adapt and survive. Whereas responses are mostly mediated by slow changes in protein levels through genes, rapid changes can be achieved by chemically modifying proteins in order to modulate their roles in the cell. These post-translational modifications (PTMs) are essential to all forms of life on Earth and come in different flavours. Two of the most common are: 1) phosphorylation, carried out by protein kinases, and 2) ubiquitination, carried out by ubiquitin ligases. Recently, my laboratory and others discovered that the molecule ubiquitin itself is subject to phosphorylation. The modification is carried out by a kinase named PINK1 that is involved in a quality control pathway essential for the long-term survival of neurons. This protein can be found in nearly all animals, from insects to humans. Phosphorylated ubiquitin is a key signal in cells for the activation of parkin, a ubiquitin ligase that is involved in a number of cellular processes including protein quality control, neuronal survival, resistance to bacterial pathogens, and sugar/lipid metabolism.***I hypothesize that PINK1 is the first member of a family of kinases that phosphorylate ubiquitin. The long-term objective of my research program is to characterize the family of ubiquitin kinases at the molecular structure level. My laboratory uses a wide-range of structural biology methods including X-ray crystallography, which enables us to determine the 3D structure of enzymes with very high definition. My first aim is to determine how PINK1 recognizes ubiquitin and adds a phosphate on a specific residue. My second aim is to identify and study other ubiquitin kinases, by characterizing where and how they modify ubiquitin. These studies define my research program on understanding how enzymes like ligases and kinases alter other proteins, and how PTMs regulate cell survival and function.**