Understanding ubiquitin transfer for a novel class of E3 ubiquitin ligases

The regulated destruction of proteins is central to processes such as cell cycle progression, signal transduction, and innate immunity. In mammalian cells this destruction of proteins is governed by enzymes tknown as E3 ubiquitin ligases. E3 ubiquitin ligases mark proteins for destruction by attaching a small protein known as ubiquitin to them in a process known as ubiquitination. IpaH proteins are a newly identified class of E3 ubiquitin ligases encoded by pathogenic bacteria. Bacteria hijack the ubiquitin system of mammalian cells that they infect, using IpaH proteins to destroy proteins that interfere with the pathogens survival. The mechanics of ubiquitin transfer for some E3 ligases are well defined; however, the mechanisms by which IpaH proteins transfer ubiquitin is poorly understood. IpaH proteins have activities that are unique among E3 ubiquitin ligases. These unique properties serve as entry points to study how these enzymes work. A complete understanding of how IpaHs transfer ubiquitin will aid in our understanding of ubiquitin transfer in general. In addition, understanding the mode of action of these enzymes is fundamental for the rational development of small molecule based therapies to target IpaHs and combat the devestating diseases caused by pathogens that encode IpaHs.