Mechanisms of Ubiquitin Transfer and Regulation
EMSL Project ID
25658
Abstract
Protein ubiquitination is a powerful regulatory process that influences nearly every aspect of eukaryotic cell biology. Pathways ranging from cell-cycle progression and differentiation to DNA repair to vesicle budding all rely on regulated modification of target proteins by ubiquitin. It is not surprising that aberrations in critical ubiquitin pathways are implicated in the etiology and progression of numerous human diseases including tumorigenesis and neurodegenerative diseases. In addition, recent research has revealed that many pathogenic bacteria have evolved mechanisms designed to exploit or interfere with eukaryotic ubiquitination pathways in order to modulate the immune response of an animal or plant cell host and enhance infectivity. Despite the importance of ubiquitination for cell viability and in the interaction between pathogenic bacteria and eukaryotic hosts, surprisingly little is understood regarding the mechanisms of protein ubiquitination. A target protein can be mono-ubiquitinated or modified by ubiquitin polymers that can vary in length and linkage specificity. These differences determine the ultimate fate of a protein and can alter cellular location of a particular protein, protein activity, the interaction with other macromolecules, or doom the protein for destruction. To date, simple models to explain ubiquitin transfer have dominated the literature, but recent work suggests the basic assumptions as to how proteins assemble to facilitate protein ubiquitination must be re-examined. This proposal is aimed at understanding at the molecular level the underlying network of protein interactions that governs the assembly of an active ubiquitin-ligase complex and how these interactions influence the products of ubiquitin transfer reaction. In addition, our interests in macromolecular complexes involving ubiquitin transfer and recognition are leading us to develop new systems that explore the relationship between pathogenic bacteria and their hosts. This work focuses on bacterial effector proteins that have evolved to interfere with the host ubiquitination machinery in order to enhance infectivity.
Project Details
Project type
Large-Scale EMSL Research
Start Date
2007-05-23
End Date
2010-09-30
Status
Closed
Released Data Link
Team
Principal Investigator
Team Members