University of Helsinki
Supervisor: Adrian Goldman
Trimeric Autotransporter Adhesins (TAAs) compose a large family of proteins from Gram-negative bacteria that are among the first to be expressed on the cell surface during bacterial invasion. They consist of a signal peptide, an N-terminal passenger domain comprising a globular head and a coiled-coil stalk, and the 12 strand β-barrel C-terminal translocation domain (50 residues per monomer) (Linke et al., Trends Microbiol. 14:264-70, Nummelin et al., EMBO J. 23:701-11). After Sec-dependent translocation across the inner membrane, the translocation domain is assembled with the help of the Bam complex and inserted into the outer membrane (OM). The final step is transportation of the passenger domain through the β-barrel to the outside of the cell, but the mechanism of this step remains unclear (Dautin et al., Annu. Rev. Microbiol. 61:89-112). YadA is a prototypical member of the TAA protein family, which is expressed by three species of yersiniae pathogenic to humans. They are Y. enterocolitica, Y. Pseudotuberculosis, enteropathogens causing gastrointestinal infection and Y. pestis causing plague. Other TAAs include the immunoglobulin-binding Eibs that occur in E. coli, such as EibG from certain enterohaemorrhagic E. coli (EHEC) strains that produce shiga-toxin (Merkel et al., Infect. Immun. 78:3625-36).
The aim of my Ph.D. thesis is to understand the nature of TAAs folding, translocation and interactions with host ligands. Crystallisation of TAAs complexes with ligands will allow the development of new antibacterials that target TAAs - both their folding and interactions with host proteins. Compounds that interfere with folding would also decrease biofilm formation, a major problem in bacterial virulence. Being able to deliver effector proteins, such as enzymes, via a TAA system to the surface of the cell will allow the use of whole bacteria as a substrate in technological processes rather than purified proteins.