Yersinia pestis, the causative agent of plague, is a highly pathogenic organism that spreads rapidly and causes extremely high human mortality. Although it is sensitive to a restricted panel of antibiotics, its extraordinary pathogenicity, the potential weaponization of aerosolized bacteria with bio-engineered antibiotic resistance, and the lack of an effective vaccine or therapy are major concerns, contributing to its classification as a Tier 1 Biothreat Agent. The outer membrane protein Ail is a Y. pestis virulence factor and a prime candidate for therapeutic development due to its two principal activities: (i) mediating the adhesion of Y. pestis bacteria to host cells, and (ii) providing resistance to human complement. This project focuses on understanding its adhesion activity as a step towards its development as a novel therapeutic target. The working hypothesis is that Ail binds one or more host proteins, triggering host intracellular signaling cascades and the translocation of bacterial factors into the host cell that block phagocytosis and enable bacteria to survive extracellularly. Adhesion is the first key step in this series of events;however, how does Ail mediate bacterial adhesion to human cells? Molecular information is lacking.
The specific aims of this project are designed to fill this glaring gap by obtaining functional and structural information about the adhesion activity of Ail and the interactions with its human host partners.

Public Health Relevance

The overall goal of this project is to understand how Yersinia pestis, the causative agent of plague, attaches to human host cells and evades the human immune system. The potential use of plague as a biological weapon is of major concern and our studies will provide important information for therapeutic developments.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Macromolecular Structure and Function B Study Section (MSFB)
Program Officer
Chin, Jean
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Sanford-Burnham Medical Research Institute
La Jolla
United States
Zip Code
Yao, Yong; Nisan, Danielle; Fujimoto, Lynn M et al. (2016) Characterization of the membrane-inserted C-terminus of cytoprotective BCL-XL. Protein Expr Purif 122:56-63
Gong, Xiao-Min; Ding, Yi; Yu, Jinghua et al. (2015) Structure of the Na,K-ATPase regulatory protein FXYD2b in micelles: implications for membrane-water interfacial arginines. Biochim Biophys Acta 1848:299-306
Bartra, Sara Schesser; Ding, Yi; Miya Fujimoto, L et al. (2015) Yersinia pestis uses the Ail outer membrane protein to recruit vitronectin. Microbiology 161:2174-2183
Yao, Yong; Fujimoto, Lynn M; Hirshman, Nathan et al. (2015) Conformation of BCL-XL upon Membrane Integration. J Mol Biol 427:2262-70
Cheng, Xi; Jo, Sunhwan; Qi, Yifei et al. (2015) Solid-State NMR-Restrained Ensemble Dynamics of a Membrane Protein in Explicit Membranes. Biophys J 108:1954-62
Ding, Yi; Fujimoto, L Miya; Yao, Yong et al. (2015) Solid-state NMR of the Yersinia pestis outer membrane protein Ail in lipid bilayer nanodiscs sedimented by ultracentrifugation. J Biomol NMR 61:275-86
Tian, Ye; Schwieters, Charles D; Opella, Stanley J et al. (2015) A Practical Implicit Membrane Potential for NMR Structure Calculations of Membrane Proteins. Biophys J 109:574-85
Marassi, Francesca M; Ding, Yi; Schwieters, Charles D et al. (2015) Backbone structure of Yersinia pestis Ail determined in micelles by NMR-restrained simulated annealing with implicit membrane solvation. J Biomol NMR 63:59-65
Ding, Yi; Fujimoto, L Miya; Yao, Yong et al. (2015) Influence of the lipid membrane environment on structure and activity of the outer membrane protein Ail from Yersinia pestis. Biochim Biophys Acta 1848:712-20
Volkmann, N; Marassi, F M; Newmeyer, D D et al. (2014) The rheostat in the membrane: BCL-2 family proteins and apoptosis. Cell Death Differ 21:206-15

Showing the most recent 10 out of 15 publications