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Lacy Lab Contact

Vanderbilt University Medical Center
Department of Microbiology and Immunology
A-5301 Medical Center North
1161 21st Avenue South
Nashville, TN 37232-2363
tel: (615) 343-9080; email: borden.lacy -at- vanderbilt.edu

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Research

Pathogenic bacteria have evolved distinct mechanisms for delivering toxins and other virulence factors across cellular membranes and into the cytosol of host cells. We are interested in understanding the mechanism of entry in several toxin systems- the clostridial neurotoxins, the clostridial cytotoxins and the vacuolating toxin of Helicobacter pylori. Our experimental approach involves the combination of functional studies with structural methods (X-ray crystallography, EPR spectroscopy, and electron microscopy).

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

C. Gonzalez-Rivera1, K. A. Gangwer1, M. S. McClain, I. M. Eli, M. G. Chambers, M. D. Ohi, D. B. Lacy2, T. L. Cover2. (2010) Reconstitution of Helicobacter pylori VacA toxin from purified components. Biochemistry, 49, 5743-52.

R. N. Pruitt, M. G. Chambers, K. Ng, M. D. Ohi, and D. B. Lacy. (2010) Structural organization of the functional domains of Clostridium difficile toxins A and B. Proc Natl Acad Sci U S A. 107, 13467-72.

J. Schmitt, A. Karalewitz, D. A. Benefield, D. J. Mushrush, R. N. Pruitt, B. W. Spiller, J. T. Barbieri, D. B. Lacy (2010) A structural analysis of botulinum neurotoxin type G receptor binding. Biochemistry, 49, 5200-5.

S. E. Ivie, M. S. McClain, H. M. S. Algood, D. B. Lacy, T. L. Cover (2010) Analysis of a beta-helical region in the p55 domain of Helicobacter pylori vacuolating toxin. BMC Microbiol. 10:60. BMC Microbiol. 10, 60.

R. N. Pruitt, B. Chagot, M. Cover, W. J. Chazin, B. Spiller, D. B. Lacy (2009) Structure-function analysis of inositol hexakisphosphate-induced autoprocessing in Clostridium difficile toxin A. J Biol Chem, 284, 21934-40.

A. Fischer, D. J. Mushrush, D. B. Lacy, and M. Montal (2008) Botulinum neurotoxin devoid of receptor binding domain translocates active protease. PLoS Pathog, 4, 12.

S. E. Ivie, M. S. McClain, V. J. Torres, H. M. S. Algood, D. B. Lacy, R. Yang, S. R. Blanke, T. L. Cover (2008) A Helicobacter pylori VacA subdomain required for intracellular toxin activity and assembly of functional oligomeric complexes. Infection and Immunity, 76, 2843-51.

K. A. Gangwer, D. J. Mushrush, D. L. Stauff, B.Spiller, M. S. McClain, T. L. Cover, D. B. Lacy (2007) Crystal Structure of the Helicobacter pylori Vacuolating Toxin p55 Domain. Proc Natl Acad Sci U S A, 104, 16293-8.

H. M. Scobie, J. M. Marlett, G. J. Rainey, D. B. Lacy, R. J. Collier, J. A. Young (2007) Anthrax Toxin Receptor 2 Determinants that Dictate the pH Threshold of Toxin Pore Formation. PLoS ONE, 2, e329.

H. M. Scobie, D. J. Wigelsworth, J. M. Marlett, D. Thomas, G. J. Rainey, D. B. Lacy, M. Manchester, R. J. Collier, J. A. Young (2006) Anthrax toxin receptor 2-dependent lethal toxin killing in vivo. PLoS Pathog, 2, 949-55.

R. A. Melnyk, K. M. Hewitt, D. B. Lacy, H. C. Lin, C. R. Gessner, S. Li, V. L. Woods Jr, R. J. Collier (2006) Structural determinants for the binding of anthrax lethal factor to oligomeric protective antigen. J Biol Chem. 281, 1630-5.

D. B. Lacy, H. C. Lin, R. A. Melnyk, O. Schueler-Furman, L. Reither, K. Cunningham, D. Baker, R. J. Collier (2005) A model of anthrax toxin lethal factor bound to protective antigen. Proc Natl Acad Sci U S A. 102, 16409-14.

B. A. Krantz, R. A. Melnyk, S. Zhang, S. J. Juris, D. B. Lacy, Z. Wu, A. Finkelstein, R. J. Collier (2005) A phenylalanine clamp catalyzes protein translocation through the anthrax toxin pore. Science 309, 777-81.

D. B. Lacy, D. J. Wigelsworth, R. A. Melnyk, S. C. Harrison, and R. J. Collier (2004) 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, 13147-51.

D. J. Wigelsworth , B. A. Krantz, K. A. Christensen, D. B. Lacy, S. J. Juris, and R. J. Collier (2004) Binding stoichiometry and kinetics of the interaction of a human anthrax toxin receptor, CMG2, with protective antigen. J. Biol. Chem. 279, 23349-56.

D. B. Lacy, D. J. Wigelsworth, H. M. Scobie, J. A. T. Young, and R. J. Collier (2004) 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, 6367-72.

M. Mourez, M. Yan, D. B. Lacy, L. Dillon, L. Bentsen, A. Marpoe, C. Maurin, E. Hotze, D. Wigelsworth, R. Pimental, J. D. Ballard, R. J. Collier, and R. K. Tweten (2003) Mapping dominant-negative mutations of anthrax protective antigen by scanning mutagenesis. Proc Natl Acad Sci U S A 100, 13803-8.

D. B. Lacy and R. J. Collier (2002) Structure and function of anthrax toxin. Curr Top Microbiol Immunol. 271, 61-85.

M. Mourez, D. B. Lacy, K. Cunningham, R. Legmann, B. R. Sellman, J. Mogridge, and R. J. Collier (2002) 2001: a year of major advances in anthrax toxin research. Trends Microbiol. 10, 287-93.

K. Cunningham, D. B. Lacy, J. Mogridge, R. J. Collier (2002) Mapping the lethal factor and edema factor binding sites on oligomeric anthrax protective antigen. Proc Natl Acad Sci U S A 99, 7049-53.

J. Mogridge, K. Cunningham, D. B. Lacy, M. Mourez, and R. J. Collier (2002) 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, 7045-8.

D. B. Lacy, M. Mourez, A. Fouassier, and R. J. Collier (2002) Mapping the anthrax protective antigen binding site on the lethal and edema factors. J Biol Chem. 277, 3006-10.

A. D. Pannifer, T. Y. Wong, R. Schwarzenbacher, M. Renatus, C. Petosa, J. Bienkowska, D. B. Lacy, R. J. Collier, S. Park, S. H. Leppla, P. Hanna, and R. C. Liddington (2001) Crystal structure of the anthrax lethal factor. Nature 414, 229-33.

D. B. Lacy and R. C. Stevens (1999) Sequence homology and structural analysis of the clostridial neurotoxins. Journal of Molecular Biology 291, 1091-104.

D. B. Lacy and R. C. Stevens (1998) Unraveling structures and modes of action of bacterial toxins. Current Opinion in Structural Biology 8, 778-84.

D. B. Lacy, W. Tepp, A. C. Cohen, B. R. DasGupta, and R. C. Stevens (1998) The crystal structure of botulinum neurotoxin type A and implications for toxicity. Nature Structural Biology 5, 898-902.

D. B. Lacy and R. C. Stevens (1997) Recombinant expression and purification of the botulinum neurotoxin type A translocation domain. Protein Expression and Purification 11, 195-200.

M. T. Crimmins, S. Huang, L. E. Guise, and D. B. Lacy (1995) Addition of functionalized zinc copper reagents to acetylenic esters: synthesis of 2-carboalkoxy cyclohexenones. Tetrahedron Letters 36, 7061-64.

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Lab Members

Postdoctoral Fellows

Melissa Farrow, 2010-present, Ph.D. from University of Massachusetts Medical School


Graduate Students

Desiree Benefield, 2010-present, B.S. from University of Tennesee at Chattanooga.
Michelle LaFrance, 2009-present, B.S. from Brandeis University.
Nicole Chumbler, 2009-present, B.S. from Mercer University.
Rory Pruitt, 2007-present, B.A. from Huntingdon College, 2006.
Darren Mushrush, 2007-present, M.S. from Vanderbilt, 2006.
Kelly Gangwer, 2006-present, B.S. University of Miami, 2005.


Research Assisant

Stacey Seeback


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Alumni

Graduate Students

Major John Schmitt, 2007-2009, Masters Student. Present position: Instructor at Westpoint


Undergraduate Students

Reed Jones, 2010, Present position: Undergraduate Student at Rice University
Laura Hood, 2009, Present position: Undergraduate Student at University of Tennessee
Michael Cover, 2008, Present position: Medical Student at Case Western Reserve
Erica Bozeman, 2006-2007, Present position: Graduate Student at Emory University

Research Assisant

Adarsh Godbole, Present position: Pfizer


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