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Lacy, D. Borden, Ph.D.
Assistant Professor of Microbiology and Immunology
Assistant Professor of Biochemistry
Lab Url:
N/A
Phone
Number:
615-343-9080
Email Address:
borden.lacy@vanderbilt.edu
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| Office
Address |
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5144C MRBIII |
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Address |
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A-5301 MCN 37232 |
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| Research
Keywords |
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bacteria, pathogenesis, botulinum neurotoxin, Helicobacter pylori, receptor, structural biology, x-ray crystallography |
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| Research
Specialty |
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Structural biology of bacterial protein toxins and their host interactions |
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| Research
Description |
Pathogenic bacteria have evolved distinct mechanisms for delivering toxins and other virulence factors across cellular membranes and into the cytosol of host cells. One means of accomplishing this is via a three-step process: (i) receptor binding, (ii) receptor-triggered endocytosis, and (iii) membrane insertion and translocation following endosomal acidification. One of the central themes in our research is to understand the molecular basis of membrane insertion and translocation. How does a soluble protein convert to a membrane-spanning pore? How are portions of the toxin translocated through this pore to gain access to the cytosol? Can we translate the information we learn with these ‘simple’ single proteins to an understanding of how secretion and export processes occur in larger protein assemblies? In an effort to synthesize an understanding about this fundamental biological question, we have chosen to study the mechanisms of pore formation and membrane translocation for several toxin systems- including the clostridial neurotoxins and the vacuolating toxin of Helicobacter pylori.
At the same time, we are studying each toxin in the context of its host cell interactions in an effort to understand the unique contributions each virulence factor makes in human disease. To this end, the questions we are currently addressing are related to the role of receptors in mediating the toxin’s host cell tropism, trafficking, and signaling events.
Our experimental approach involves the combination of functional studies with structural methods (X-ray crystallography, EPR spectroscopy, electron microscopy, and electron diffraction). Elucidating the molecular structures and functions of these virulence factors alone and in complex with host receptors and membranes will reveal vital information about fundamental mechanisms in bacterial pathogenesis.
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| Publications
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Pruitt, RN, Chagot, B, Cover, M, Chazin, WJ, Spiller, B, Lacy, DB. Structure-function analysis of inositol hexakisphosphate-induced autoprocessing in Clostridium difficile toxin A. J Biol Chem, 284(33), 21934-40, 2009. Fischer, A, Mushrush, DJ, Lacy, DB, Montal, M. Botulinum neurotoxin devoid of receptor binding domain translocates active protease. PLoS Pathog, 4(12), e1000245, 2008. Ivie, SE, McClain, MS, Torres, VJ, Algood, HM, Lacy, DB, Yang, R, Blanke, SR, Cover, TL. Helicobacter pylori VacA subdomain required for intracellular toxin activity and assembly of functional oligomeric complexes. Infect Immun, 76(7), 2843-51, 2008. Gangwer, KA, Mushrush, DJ, Stauff, DL, Spiller, B, McClain, MS, Cover, TL, Lacy, DB. Crystal structure of the Helicobacter pylori vacuolating toxin p55 domain. Proc Natl Acad Sci U S A, 104(41), 16293-8, 2007. Scobie, HM, Marlett, JM, Rainey, GJ, Lacy, DB, Collier, RJ, Young, JA. Anthrax toxin receptor 2 determinants that dictate the pH threshold of toxin pore formation. PLoS ONE, 2, e329, 2007. Melnyk, RA, Hewitt, KM, Lacy, DB, Lin, HC, Gessner, CR, Li, S, Woods, VL, Collier, RJ. Structural determinants for the binding of anthrax lethal factor to oligomeric
protective antigen. J Biol Chem, 281(3), 1630-5, 2006. Scobie, HM, Wigelsworth, DJ, Marlett, JM, Thomas, D, Rainey, GJ, Lacy, DB, Manchester, M, Collier, RJ, Young, JA. Anthrax Toxin Receptor 2-Dependent Lethal Toxin Killing In Vivo. PLoS Pathog, 2(10), , 2006. Krantz, BA, Melnyk, RA, Zhang, S, Juris, SJ, Lacy, DB, Wu, Z, Finkelstein, A, Collier, RJ. A phenylalanine clamp catalyzes protein translocation through the anthrax toxin
pore. Science, 309(5735), 777-81, 2005. Lacy, DB, Lin, HC, Melnyk, RA, Schueler-Furman, O, Reither, L, Cunningham, K, Baker, D, Collier, RJ. A model of anthrax toxin lethal factor bound to protective antigen. Proc Natl Acad Sci U S A, 102(45), 16409-14, 2005. Lacy, DB, Wigelsworth, DJ, Melnyk, RA, Harrison, SC, Collier, RJ. Structure of heptameric protective antigen bound to an anthrax toxin receptor:
a role for receptor in pH-dependent pore formation. Proc Natl Acad Sci U S A, 101(36), 13147-51, 2004. Lacy, DB, Wigelsworth, DJ, Scobie, HM, Young, JA, Collier, RJ. Crystal structure of the von Willebrand factor A domain of human capillary
morphogenesis protein 2: an anthrax toxin receptor. Proc Natl Acad Sci U S A, 101(17), 6367-72, 2004. Wigelsworth, DJ, Krantz, BA, Christensen, KA, Lacy, DB, Juris, SJ, Collier, RJ. Binding stoichiometry and kinetics of the interaction of a human anthrax toxin
receptor, CMG2, with protective antigen. J Biol Chem, 279(22), 23349-56, 2004. Mourez, M, Yan, M, Lacy, DB, Dillon, L, Bentsen, L, Marpoe, A, Maurin, C, Hotze, E, Wigelsworth, D, Pimental, RA, Ballard, JD, Collier, RJ, Tweten, RK. Mapping dominant-negative mutations of anthrax protective antigen by scanning
mutagenesis. Proc Natl Acad Sci U S A, 100(24), 13803-8, 2003. Cunningham, K, Lacy, DB, Mogridge, J, Collier, RJ. Mapping the lethal factor and edema factor binding sites on oligomeric anthrax
protective antigen. Proc Natl Acad Sci U S A, 99(10), 7049-53, 2002. Lacy, DB, Collier, RJ. Structure and function of anthrax toxin. Curr Top Microbiol Immunol, 271, 61-85, 2002. Lacy, DB, Mourez, M, Fouassier, A, Collier, RJ. Mapping the anthrax protective antigen binding site on the lethal and edema
factors. J Biol Chem, 277(4), 3006-10, 2002. Mogridge, J, Cunningham, K, Lacy, DB, Mourez, M, Collier, RJ. The lethal and edema factors of anthrax toxin bind only to oligomeric forms
of the protective antigen. Proc Natl Acad Sci U S A, 99(10), 7045-8, 2002. Mourez, M, Lacy, DB, Cunningham, K, Legmann, R, Sellman, BR, Mogridge, J, Collier, RJ. 2001: a year of major advances in anthrax toxin research. Trends Microbiol, 10(6), 287-93, 2002. Pannifer, AD, Wong, TY, Schwarzenbacher, R, Renatus, M, Petosa, C, Bienkowska, J, Lacy, DB, Collier, RJ, Park, S, Leppla, SH, Hanna, P, Liddington, RC. Crystal structure of the anthrax lethal factor. Nature, 414(6860), 229-33, 2001. Lacy, DB, Stevens, RC. Sequence homology and structural analysis of the clostridial neurotoxins. J Mol Biol, 291(5), 1091-104, 1999. Lacy, DB, Stevens, RC. Unraveling the structures and modes of action of bacterial toxins. Curr Opin Struct Biol, 8(6), 778-84, 1998. Lacy, DB, Tepp, W, Cohen, AC, DasGupta, BR, Stevens, RC. Crystal structure of botulinum neurotoxin type A and implications for toxicity. Nat Struct Biol, 5(10), 898-902, 1998. Lacy, DB, Stevens, RC. Recombinant expression and purification of the botulinum neurotoxin type A
translocation domain. Protein Expr Purif, 11(2), 195-200, 1997. Crimmins, MT, Huang, S, Guise, LE, Lacy DB. Addition of functionalized zinc copper reagents to acetylenic esters: synthesis of 2-carboalkoxy cyclohexenones. Tetrahedron Letters, 36, 7061-64, 1995.
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Position Details |
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