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4. Clostridioides difficile Toxin A Remodels Membranes and Mediates DNA Entry Into Cells to Activate Toll-Like Receptor 9 Signaling

Author

Chen, Xinhua, Yang, Xiaotong, de Anda, Jaime, Huang, Jun, Li, Dan, Xu, Hua, Shields, Kelsey S, Džunková, Mária, Hansen, Joshua, Patel, Ishan J, Yee, Eric U, Golenbock, Douglas T, Grant, Marianne A, Wong, Gerard CL, and Kelly, Ciarán P

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Digestive Diseases, Infectious Diseases, Emerging Infectious Diseases, 1.1 Normal biological development and functioning, Underpinning research, Animals, Anti-Bacterial Agents, Bacterial Toxins, Clostridioides difficile, Clostridium Infections, Colitis, DNA, Bacterial, Disease Models, Animal, Enterotoxins, Female, Gastrointestinal Microbiome, Humans, Immunity, Innate, Mice, Mice, Knockout, Molecular Chaperones, Signal Transduction, Toll-Like Receptor 9, Antibiotic-Associated Diarrhea and Colitis, Intestinal Inflammation, Pore Formation, SAXS, Neurosciences, Paediatrics and Reproductive Medicine, Gastroenterology & Hepatology, Clinical sciences, Nutrition and dietetics
Abstract

Background & aimsClostridioides difficile toxin A (TcdA) activates the innate immune response. TcdA co-purifies with DNA. Toll-like receptor 9 (TLR9) recognizes bacterial DNA to initiate inflammation. We investigated whether DNA bound to TcdA activates an inflammatory response in murine models of C difficile infection via activation of TLR9.MethodsWe performed studies with human colonocytes and monocytes and macrophages from wild-type and TLR9 knockout mice incubated with TcdA or its antagonist (ODN TTAGGG) or transduced with vectors encoding TLR9 or small-interfering RNAs. Cytokine production was measured with enzyme-linked immunosorbent assay. We studied a transduction domain of TcdA (TcdA57-80), which was predicted by machine learning to have cell-penetrating activity and confirmed by synchrotron small-angle X-ray scattering. Intestines of CD1 mice, C57BL6J mice, and mice that express a form of TLR9 that is not activated by CpG DNA were injected with TcdA, TLR9 antagonist, or both. Enterotoxicity was estimated based on loop weight to length ratios. A TLR9 antagonist was tested in mice infected with C difficile. We incubated human colon explants with an antagonist of TLR9 and measured TcdA-induced production of cytokines.ResultsThe TcdA57-80 protein transduction domain had membrane remodeling activity that allowed TcdA to enter endosomes. TcdA-bound DNA entered human colonocytes. TLR9 was required for production of cytokines by cultured cells and in human colon explants incubated with TcdA. TLR9 was required in TcdA-induced mice intestinal secretions and in the survival of mice infected by C difficile. Even in a protease-rich environment, in which only fragments of TcdA exist, the TcdA57-80 domain organized DNA into a geometrically ordered structure that activated TLR9.ConclusionsTcdA from C difficile can bind and organize bacterial DNA to activate TLR9. TcdA and TcdA fragments remodel membranes, which allows them to access endosomes and present bacterial DNA to and activate TLR9. Rather than inactivating the ability of DNA to bind TLR9, TcdA appears to chaperone and organize DNA into an inflammatory, spatially periodic structure.

Published
2020

10. On the nucleation of amyloid β‐protein monomer folding

Author

Lazo, Noel D, Grant, Marianne A, Condron, Margaret C, Rigby, Alan C, and Teplow, David B

Subjects
Alzheimer's Disease, Neurosciences, Dementia, Neurodegenerative, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Acquired Cognitive Impairment, Aging, Brain Disorders, Aetiology, 2.1 Biological and endogenous factors, Alzheimer Disease, Amyloid beta-Peptides, Animals, Humans, Protein Folding, Protein Structure, Secondary, Alzheimer's disease, amyloid, amyloid beta-protein, folding nucleus, protein folding, Biochemistry and Cell Biology, Computation Theory and Mathematics, Other Information and Computing Sciences, Biophysics
Abstract

Neurotoxic assemblies of the amyloid beta-protein (Abeta) have been linked strongly to the pathogenesis of Alzheimer's disease (AD). Here, we sought to monitor the earliest step in Abeta assembly, the creation of a folding nucleus, from which oligomeric and fibrillar assemblies emanate. To do so, limited proteolysis/mass spectrometry was used to identify protease-resistant segments within monomeric Abeta(1-40) and Abeta(1-42). The results revealed a 10-residue, protease-resistant segment, Ala21-Ala30, in both peptides. Remarkably, the homologous decapeptide, Abeta(21-30), displayed identical protease resistance, making it amenable to detailed structural study using solution-state NMR. Structure calculations revealed a turn formed by residues Val24-Lys28. Three factors contribute to the stability of the turn, the intrinsic propensities of the Val-Gly-Ser-Asn and Gly-Ser-Asn-Lys sequences to form a beta-turn, long-range Coulombic interactions between Lys28 and either Glu22 or Asp23, and hydrophobic interaction between the isopropyl and butyl side chains of Val24 and Lys28, respectively. We postulate that turn formation within the Val24-Lys28 region of Abeta nucleates the intramolecular folding of Abeta monomer, and from this step, subsequent assembly proceeds. This model provides a mechanistic basis for the pathologic effects of amino acid substitutions at Glu22 and Asp23 that are linked to familial forms of AD or cerebral amyloid angiopathy. Our studies also revealed that common C-terminal peptide segments within Abeta(1-40) and Abeta(1-42) have distinct structures, an observation of relevance for understanding the strong disease association of increased Abeta(1-42) production. Our results suggest that therapeutic approaches targeting the Val24-Lys28 turn or the Abeta(1-42)-specific C-terminal fold may hold promise.

Published
2005

11. On the nucleation of amyloid beta-protein monomer folding.

Author

Lazo, Noel D, Grant, Marianne A, Condron, Margaret C, Rigby, Alan C, and Teplow, David B

Subjects
Animals, Humans, Alzheimer Disease, Protein Structure, Secondary, Protein Folding, Amyloid beta-Peptides, Alzheimer's disease, amyloid, amyloid beta-protein, folding nucleus, protein folding, Biophysics, Biochemistry and Cell Biology, Computation Theory and Mathematics, Other Information and Computing Sciences
Abstract

Neurotoxic assemblies of the amyloid beta-protein (Abeta) have been linked strongly to the pathogenesis of Alzheimer's disease (AD). Here, we sought to monitor the earliest step in Abeta assembly, the creation of a folding nucleus, from which oligomeric and fibrillar assemblies emanate. To do so, limited proteolysis/mass spectrometry was used to identify protease-resistant segments within monomeric Abeta(1-40) and Abeta(1-42). The results revealed a 10-residue, protease-resistant segment, Ala21-Ala30, in both peptides. Remarkably, the homologous decapeptide, Abeta(21-30), displayed identical protease resistance, making it amenable to detailed structural study using solution-state NMR. Structure calculations revealed a turn formed by residues Val24-Lys28. Three factors contribute to the stability of the turn, the intrinsic propensities of the Val-Gly-Ser-Asn and Gly-Ser-Asn-Lys sequences to form a beta-turn, long-range Coulombic interactions between Lys28 and either Glu22 or Asp23, and hydrophobic interaction between the isopropyl and butyl side chains of Val24 and Lys28, respectively. We postulate that turn formation within the Val24-Lys28 region of Abeta nucleates the intramolecular folding of Abeta monomer, and from this step, subsequent assembly proceeds. This model provides a mechanistic basis for the pathologic effects of amino acid substitutions at Glu22 and Asp23 that are linked to familial forms of AD or cerebral amyloid angiopathy. Our studies also revealed that common C-terminal peptide segments within Abeta(1-40) and Abeta(1-42) have distinct structures, an observation of relevance for understanding the strong disease association of increased Abeta(1-42) production. Our results suggest that therapeutic approaches targeting the Val24-Lys28 turn or the Abeta(1-42)-specific C-terminal fold may hold promise.

Published
2005

14. Contributors

Author

Abdel-Wahab, Omar, primary, Abrahm, Janet L., additional, Adams, Sharon, additional, Adewoye, Adeboye H., additional, Allen, Carl, additional, Ambinder, Richard F., additional, Anasetti, Claudio, additional, Anastasi, John, additional, Anderson, Julia A., additional, Antin, Joseph H., additional, Antony, Aśok C., additional, Araten, David J., additional, Armand, Philippe, additional, Armstrong, Gillian, additional, Armstrong, Scott A., additional, Arnold, Donald M., additional, Artz, Andrew S., additional, Awan, Farrukh T., additional, Baglin, Trevor P., additional, Benson, Don M., additional, Benz, Edward J., additional, Berliner, Nancy, additional, Bhagat, Govind, additional, Bhardwaj, Nina, additional, Bhatia, Ravi, additional, Bhatia, Smita, additional, Bhatt, Mihir D., additional, Bhatt, Vijaya Raj, additional, Bitan, Menachem, additional, Blinderman, Craig D., additional, Bollard, Catherine M., additional, Braun, Benjamin S., additional, Brenner, Malcolm K., additional, Brittenham, Gary M., additional, Brodsky, Robert A., additional, Brown, Myles, additional, Broxmeyer, Hal E., additional, Brummel-Ziedins, Kathleen, additional, Brunner, Andrew M., additional, Buadi, Francis K., additional, Burkhardt, Birgit, additional, Burns, Melissa, additional, Byrd, John C., additional, Caimi, Paolo F., additional, Caligiuri, Michael A., additional, Canavan, Michelle, additional, Cantor, Alan B., additional, Carcao, Manuel, additional, Carroll, Michael C., additional, Carty, Shannon A., additional, Castillo, Jorge J., additional, Chan, Anthony K.C., additional, Chapin, John, additional, Chiu, April, additional, Chute, John P., additional, Clark, David B., additional, Coates, Thomas D., additional, Cogle, Christopher R., additional, Connell, Nathan T., additional, Cooke, Elizabeth, additional, Cooley, Sarah, additional, Corradini, Paolo, additional, Creager, Mark A., additional, Creger, Richard J., additional, Cromwell, Caroline, additional, Crowther, Mark A., additional, Cushing, Melissa M., additional, Cutler, Corey, additional, Dang, Chi V., additional, Danial, Nika N., additional, Dave, Sandeep S., additional, DeCaprio, James A., additional, Dinauer, Mary C., additional, Dinner, Shira, additional, Diz-Küçükkaya, Reyhan, additional, Dodd, Roger Y., additional, Donato, Michele L., additional, Dorshkind, Kenneth, additional, Dotti, Gianpietro, additional, Dror, Yigal, additional, Dunleavy, Kieron, additional, Dvorak, Christopher C., additional, Ebert, Benjamin L., additional, Eck, Michael J., additional, Eikelboom, John W., additional, Epperla, Narendranath, additional, Ershler, William B., additional, Evans, William E., additional, Faderl, Stefan, additional, Ferrara, James L.M., additional, Filipovich, Alexandra Hult, additional, Fischer, Martin, additional, Fredenburgh, James C., additional, Friedman, Kenneth D., additional, Fuchs, Ephraim, additional, Fuller, Stephen J., additional, Gailani, David, additional, Galipeau, Jacques, additional, Gallagher, Patrick G., additional, Ganapathi, Karthik A., additional, Gardner, Lawrence B., additional, Gee, Adrian P., additional, Gerson, Stanton L., additional, Gertz, Morie A., additional, Giardina, Patricia J., additional, Gibson, Christopher J., additional, Golan, Karin, additional, Golub, Todd R., additional, Gonzales, Matthew J., additional, Gotlib, Jason, additional, Gottschalk, Stephen, additional, Grant, Marianne A., additional, Graubert, Timothy A., additional, Gregg, Xylina T., additional, Gribben, John G., additional, Gross, Dawn M., additional, Gruber, Tanja A., additional, Guitart, Joan, additional, Gurbuxani, Sandeep, additional, Gur-Cohen, Shiri, additional, Gutierrez, Alejandro, additional, Hamadani, Mehdi, additional, Hari, Parameswaran N., additional, Hartwig, John H., additional, Hayman, Suzanne R., additional, Hayward, Catherine P.M., additional, Hebbel, Robert P., additional, Heslop, Helen E., additional, Hillis, Christopher, additional, Hillyer, Christopher D., additional, Ho, Karin, additional, Hockenbery, David M., additional, Hoffman, Ronald, additional, Hogg, Kerstin E., additional, Holtan, Shernan G., additional, Horny, Hans-Peter, additional, Hsu, Yen-Michael S., additional, Hunter, Zachary R., additional, Huntington, James A., additional, Iancu-Rubin, Camelia, additional, Iqbal, Ali, additional, Isenman, David E., additional, Israels, Sara J., additional, Italiano, Joseph E., additional, Jaffe, Elaine S., additional, Jaffer, Iqbal H., additional, Jagannath, Sundar, additional, Jäger, Ulrich, additional, Jain, Nitin, additional, James, Paula, additional, Jeha, Sima, additional, Jordan, Michael B., additional, Josephson, Cassandra D., additional, Jung, Moonjung, additional, Kager, Leo, additional, Kambayashi, Taku, additional, Kanakry, Jennifer A., additional, Kantarjian, Hagop M., additional, Kaplan, Jason, additional, Karafin, Matthew S., additional, Karsan, Aly, additional, Kaufman, Randal J., additional, Kaufman, Richard M., additional, Keller, Frank G., additional, Kelly, Kara M., additional, Kessler, Craig M., additional, Key, Nigel S., additional, Keyzner, Alla, additional, Khandoga, Alexander G., additional, Khanna-Gupta, Arati, additional, Khatib-Massalha, Eman, additional, Klein, Harvey G., additional, Knoechel, Birgit, additional, Kollet, Orit, additional, Konkle, Barbara A., additional, Kontoyiannis, Dimitrios P., additional, Koreth, John, additional, Koretzky, Gary A., additional, Kotecha, Dipak, additional, Kremyanskaya, Marina, additional, Kumari, Anju, additional, Kuzel, Timothy M., additional, Küppers, Ralf, additional, Lacy, Martha Q., additional, Ladas, Elana, additional, Landier, Wendy, additional, Lapid, Kfir, additional, Lapidot, Tsvee, additional, Larson, Peter J., additional, Levi, Marcel, additional, Lewis, Russell E., additional, Liebman, Howard A., additional, Lillicrap, David, additional, Lim, Wendy, additional, Lin, Judith C., additional, Lindblad, Robert, additional, Lip, Gregory Y.H., additional, Little, Jane A., additional, Lohr, Jens G., additional, López, José A., additional, Luscinskas, Francis W., additional, Maciejewski, Jaroslaw P., additional, Majhail, Navneet S., additional, Manches, Olivier, additional, Mandle, Robert J., additional, Mann, Kenneth G., additional, Manno, Catherine S., additional, Marcogliese, Andrea N., additional, Mariani, Guglielmo, additional, Marincola, Francesco M., additional, Mascarenhas, John, additional, Massberg, Steffen, additional, McEver, Rodger P., additional, McGrath, Emer, additional, McKinney, Matthew S., additional, Mehta, Rohtesh S., additional, Mentzer, William C., additional, Merlini, Giampaolo, additional, Merryman, Reid, additional, Michel, Marc, additional, Migliaccio, Anna Rita, additional, Miller, Jeffrey S., additional, Mims, Martha P., additional, Mondoro, Traci Heath, additional, Moorehead, Paul, additional, Muniz, Luciana R., additional, Munshi, Nikhil C., additional, Najfeld, Vesna, additional, Nayak, Lalitha, additional, Nazy, Ishac, additional, Neff, Anne T., additional, Ness, Paul M., additional, Notarangelo, Luigi D., additional, O'Brien, Sarah H., additional, O'Connor, Owen A., additional, O'Donnell, Martin, additional, Olson, Amanda, additional, Orkin, Stuart H., additional, Pai, Menaka, additional, Pai, Sung-Yun, additional, Paidas, Michael, additional, Panch, Sandhya R., additional, Pande, Reena L., additional, Papayannopoulou, Thalia, additional, Parikh, Rahul, additional, Petersdorf, Effie W., additional, Peterson, Shane E., additional, Pittaluga, Stefania, additional, Ponce, Doris M., additional, Popolo, Laura, additional, Prchal, Josef T., additional, Pui, Ching-Hon, additional, Puigserver, Pere, additional, Rak, Janusz, additional, Ramos, Carlos A., additional, Rand, Jacob H., additional, Rand, Margaret L., additional, Rao, Dinesh S., additional, Ravandi, Farhad, additional, Rawlings, David J., additional, Reddy, Pavan, additional, Reding, Mark T., additional, Reiter, Andreas, additional, Rice, Lawrence, additional, Riese, Matthew J., additional, Ritchey, Arthur Kim, additional, Roberts, David J., additional, Roman, Elizabeth, additional, Rooney, Cliona M., additional, Rosen, Steven T., additional, Rosenthal, David S., additional, Rossmann, Marlies P., additional, Rot, Antal, additional, Rowley, Scott D., additional, Rubnitz, Jeffrey E., additional, Rydz, Natalia, additional, Salama, Mohamed E., additional, Sauk, Steven, additional, Saunthararajah, Yogen, additional, Savage, William, additional, Scadden, David, additional, Schaefer, Kristen G., additional, Schiffman, Fred, additional, Schneidewend, Robert, additional, Schrier, Stanley L., additional, Schuchman, Edward H., additional, Scullion, Bridget Fowler, additional, Selvaggi, Kathy J., additional, Senoo, Keitaro, additional, Shaheen, Montaser, additional, Shaz, Beth H., additional, Shelburne, Samuel A., additional, Shpall, Elizabeth J., additional, Shurin, Susan B., additional, Siegal, Deborah, additional, Silberstein, Leslie E., additional, Silberstein, Lev, additional, Silverstein, Roy L., additional, Sloan, Steven R., additional, Smith, Franklin O., additional, Smith, James W., additional, Smith, Katy, additional, Steensma, David P., additional, Steinberg, Martin H., additional, Stock, Wendy, additional, Storry, Jill R., additional, Stramer, Susan L., additional, Strauss, Ronald G., additional, Stroncek, David F., additional, Taylor, Justin, additional, Thota, Swapna, additional, Treon, Steven P., additional, Tulpule, Anil, additional, Valdes, Roberto Ferro, additional, Valent, Peter, additional, Vedantham, Suresh, additional, Vercellotti, Gregory M., additional, Verneris, Michael R., additional, Vichinsky, Elliott P., additional, von Andrian, Ulrich H., additional, Vose, Julie M., additional, Wagner, Andrew J., additional, Wang, Ena, additional, Wang, Jia-huai, additional, Warkentin, Theodore E., additional, Wasserstein, Melissa P., additional, Webster, Ann, additional, Weisdorf, Daniel J., additional, Weitz, Jeffrey I., additional, Westhoff, Connie M., additional, Wheeler, Allison P., additional, Widick, Page, additional, Wiley, James S., additional, William, Basem M., additional, Williams, David A., additional, Wilson, Wyndham H., additional, Wolfe, Joanne, additional, Wolgast, Lucia R., additional, Wood, Deborah, additional, Wu, Jennifer, additional, Yahalom, Joachim, additional, Yee, Donald L., additional, Younes, Anas, additional, Young, Neal S., additional, and Zeller, Michelle P., additional

Published
2018
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31. Familial Alzheimer's disease mutations alter the stability of the amyloid [beta]-protein monomer folding nucleus

Author

Grant, Marianne A., Lazo, Noel D., Lomakin, Aleksey, Condron, Margaret M., Arai, Hiromi, Yamin, Ghiam, Rigby, Alan C., and Teplow, David B.

Subjects
Monomers -- Properties, Glycoproteins -- Properties, Protein folding -- Evaluation, Alzheimer's disease -- Genetic aspects, Science and technology
Abstract

Amyloid [beta]-protein (A[beta]) oligomers may be the proximate neurotoxins in Alzheimer's disease (AD). Recently, to elucidate the oligomerization pathway, we studied A[beta] monomer folding and identified a decapeptide segment of A[beta], [sup.21]Ala-[sup.22]Glu-[sup.23]Asp-[sup.24] Val-[sup.25]Gly-[sup.26]Ser-[sup.27]Asn-[sup.28]Lys-[sup.29]Gly-[sup.30]Ala, within which turn formation appears to nucleate monomer folding. The turn is stabilized by hydrophobic interactions between Val-24 and Lys-28 and by long-range electrostatic interactions between Lys-28 and either Glu-22 or Asp-23. We hypothesized that turn destabilization might explain the effects of amino acid substitutions at Glu-22 and Asp-23 that cause familial forms of AD and cerebral amyloid angiopathy. To test this hypothesis, limited proteolysis, mass spectrometry, and solution-state NMR spectroscopy were used here to determine and compare the structure and stability of the A[beta](21-30) turn within wild-type A[beta] and seven clinically relevant homologues. In addition, we determined the relative differences in folding free energies ([DELTA][DELTA][G.sub.f]) among the mutant peptides. We observed that all of the disease-associated amino acid substitutions at Glu-22 or Asp-23 destabilized the turn and that the magnitude of the destabilization correlated with oligomerization propensity. The Ala21Gly (Flemish) substitution, outside the turn proper (Glu-22-Lys-28), displayed a stability similar to that of the wild-type peptide. The implications of these findings for understanding A[beta] monomer folding and disease causation are discussed.

Published
2007

33. Lysine 5 and phenylalanine 9 of the factor IX omega-loop interact with phosphatidyslserine in a membrane-mimetic environment

Author

Grant, Marianne A., Baikeev, Roustem F., Gilbert, Gary F., and Rigby, Alan C.

Subjects
Hemophilia B -- Research, Phenylalanine -- Chemical properties, Lysine -- Chemical properties, Biological sciences, Chemistry
Abstract

The reagent and Membrane-Mimetic Environment in which Lys5, Leu6, Phe9, AND Va110 preferentially interact with C6PS are discussed. This helps us correlate known hemophilia B mutations of factor IX at Lys5 or Phe9 with impaired phosphatidylserine interaction.

Published
2004

43. P-23 Hospice pride

Author

Allen, Gemma, primary, Hudson, Sharon, additional, Spearing, Alice, additional, Jones, Mark, additional, McArthur, Suzanne, additional, Fryer, Jenni, additional, and Grant, Marianne, additional

Published
2019
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