of Eukaryotic Cell
is a gram-negative enteric pathogen that causes bacillary dysentery (shigellosis),
which continues to be an important worldwide public health problem. An essential
step in the pathogenesis of shigellosis is bacterial invasion of the epithelial
cells that line the colon. Invasion plasmid antigen C (IpaC) is the major
effector protein that subverts normal epithelial cell signaling to promote
Shigella uptake. Picking's research group and others have made
a number of advances in understanding the structure-function relationship
of IpaC; however, there has been little focus thus far on determining the
precise protein chemistry of IpaC-directed epithelial cell invasion. This
is partly due to difficulties in purifying and handling this protein. The
long-rang goal of the Picking laboratory group is to determine the precise
functional and structural organization of IpaC and to elucidate the molecular
and structural basis for IpaC interaction with and subversion of epithelial
cell signaling molecules.
Picking is working to determine the sequence, structural and physical features present in the IpaC N-terminal domain that are involved in its translocation to the host cell membrane. His group is determining the molecular basis for the role of the IpaC C-terminus in directing vascular escape of internalized Shigella and subverting the host cell signals that control the host cell cytoskeleton. They are also striving to generate crystals ( or co-crystals) of IpaC and IpaC fragments for high-resolution structure analysis.
Picking and his research group hope that this work will reveal important underlying principles of the mechanism by which Shigella promotes an epithelial cell to become phagocytic for the benefit of the pathogen. This could lead to identifying potential targets for chemotherapeutic control of infection by Shigella and related human pathogens. Lastly, by determining the biochemical and structural basis for IpaC function, it may be possible to device ways to use this protein for beneficial purposes. This protein is not toxic to mammalian cells, so it may have the ability to present antigens to the mucosal immune system.
Dr. Picking graduated from the COBRE program in 2004; he has been awarded two NIH R-01 grants, including "Structure and Function of IpaC from Shigella flexneri." He was promoted to full professor in 2007.