Bacterial Contact-Dependent Inhibition Protein Binds near the Open Lateral Gate in BamA Prior to Toxin Translocation.

Contact-dependent inhibition (CDI) is a mechanism of interbacterial competition in Gram-negative bacteria. The critical component of CDI systems is a large protein named CdiA; it forms a filament on the bacterial cell surface and contains a toxin domain at its C-terminal end. Upon binding to a receptor protein on the surface of a neighboring cell, CdiA delivers the toxin domain through the outer membrane of the neighboring bacterium. The mechanism of that delivery process is poorly understood. We have characterized how CdiA from E. coli EC93 binds to its receptor, BamA, to understand how this binding event might initiate the process of toxin delivery. BamA is an essential protein that assembles ß-barrel proteins into the outer membranes of all Gram-negative bacteria; this assembly process depends on BamA's unique ability to open laterally in the lipid bilayer through a gate in its own membrane-embedded ß-barrel. Through site-specific photo-cross-linking and mutational analysis, we demonstrate that the BamA-CdiA interaction depends on a small number of non-conserved amino acids on the extracellular surface of BamA, but the protein interface extends over a region near BamA's lateral gate. We further demonstrate that BamA's lateral gate can open without disrupting the interaction with CdiA. CdiA thus appears to initially engage BamA in a manner that could allow it to utilize BamA's lateral gate in subsequent steps in the toxin translocation process.

"Biliary Diseases with Pancreatic Counterparts": Cross-sectional Imaging Findings.

On the basis of the similarities in the histopathologic findings and the clinical-biologic behaviors of select biliary and pancreatic conditions, a new disease concept, "biliary diseases with pancreatic counterparts," has been proposed. Both nonneoplastic and neoplastic pathologic conditions of the biliary tract have their counterparts in the pancreas. Immunoglobulin G4 (IgG4)-related sclerosing cholangitis is the biliary manifestation of IgG4-related sclerosing disease, and type 1 autoimmune pancreatitis is its pancreatic counterpart. People with chronic alcoholism can develop peribiliary cysts and fibrosis as well as pancreatic fibrosis and chronic pancreatitis simultaneously. Pancreatic ductal adenocarcinoma, intraductal papillary mucinous neoplasm, and mucinous cystic neoplasm are considered pancreatic counterparts for the biliary neoplasms of extrahepatic cholangiocarcinoma, intraductal papillary neoplasm of the biliary tract, and hepatic mucinous cystic neoplasm, respectively. The anatomic proximity of the biliary tract and the pancreas, the nearly simultaneous development of both organs from the endoderm of the foregut, and the presence of pancreatic exocrine acini within the peribiliary glands surrounding the extrahepatic bile ducts are suggested as causative factors for these similarities. Interestingly, these diseases show "nearly" identical findings at cross-sectional imaging, an observation that further supports this new disease concept. New information obtained with regard to biliary diseases can be used for evaluation of pancreatic abnormalities, and vice versa. In addition, combined genetic and molecular studies may be performed to develop novel therapeutic targets. For both biliary and pancreatic diseases, imaging plays a pivotal role in initial diagnosis, evaluation of treatment response, efficacy testing of novel drugs, and long-term surveillance.