Crystal Structure of the Receptor-Binding Domain of Botulinum Neurotoxin Type HA, Also Known as Type FA or H

Yao, Guorui; Lam, Kwok-ho; Perry, Kay; Weisemann, Jasmin; Rummel, Andreas; Jin, Rongsheng

doi:10.3390/toxins9030093

Crystal Structure of the Receptor-Binding Domain of Botulinum Neurotoxin Type HA, Also Known as Type FA or H

Journal Article · Wed Mar 01 04:00:00 EST 2017 · Toxins

DOI:https://doi.org/10.3390/toxins9030093· OSTI ID:1355042

Yao, Guorui; Lam, Kwok-ho; Perry, Kay; Weisemann, Jasmin; ; Jin, Rongsheng

Botulinum neurotoxins (BoNTs), which have been exploited as cosmetics and muscle-disorder treatment medicines for decades, are well known for their extreme neurotoxicity to humans. They pose a potential bioterrorism threat because they cause botulism, a flaccid muscular paralysis-associated disease that requires immediate antitoxin treatment and intensive care over a long period of time. In addition to the existing seven established BoNT serotypes (BoNT/A–G), a new mosaic toxin type termed BoNT/HA (aka type FA or H) was reported recently. Sequence analyses indicate that the receptor-binding domain (HC) of BoNT/HA is ~84% identical to that of BoNT/A1. However, BoNT/HA responds differently to some potent BoNT/A-neutralizing antibodies (e.g., CR2) that target the HC. Therefore, it raises a serious concern as to whether BoNT/HA poses a new threat to our biosecurity. In this study, we report the first high-resolution crystal structure of BoNT/HA-HC at 1.8 Å. Sequence and structure analyses reveal that BoNT/HA and BoNT/A1 are different regarding their binding to cell-surface receptors including both polysialoganglioside (PSG) and synaptic vesicle glycoprotein 2 (SV2). Furthermore, the new structure also provides explanations for the ~540-fold decreased affinity of antibody CR2 towards BoNT/HA compared to BoNT/A1. Taken together, these new findings advance our understanding of the structure and function of this newly identified toxin at the molecular level, and pave the way for the future development of more effective countermeasures

Research Organization:: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)

Sponsoring Organization:: NIAIDFOREIGN

OSTI ID:: 1355042

Journal Information:: Toxins, Journal Name: Toxins Journal Issue: 3 Vol. 9; ISSN 2072-6651; ISSN TOXIB7

Country of Publication:: United States

Language:: ENGLISH

References (58)

Free R value: a novel statistical quantity for assessing the accuracy of crystal structures Brünger, Axel T. Nature, Vol. 355, Issue 6359 https://doi.org/10.1038/355472a0	journal	January 1992
Purification and Characterization of Botulinum Neurotoxin FA from a Genetically Modified Clostridium botulinum Strain Pellett, Sabine; Tepp, William H.; Bradshaw, Marite mSphere, Vol. 1, Issue 1 https://doi.org/10.1128/mSphere.00100-15	journal	February 2016
Structure of a Bimodular Botulinum Neurotoxin Complex Provides Insights into Its Oral Toxicity Lee, Kwangkook; Gu, Shenyan; Jin, Lei PLoS Pathogens, Vol. 9, Issue 10 https://doi.org/10.1371/journal.ppat.1003690	journal	October 2013
A Novel Strain of Clostridium botulinum That Produces Type B and Type H Botulinum Toxins Barash, Jason R.; Arnon, Stephen S. The Journal of Infectious Diseases, Vol. 209, Issue 2 https://doi.org/10.1093/infdis/jit449	journal	October 2013
Molecular Characterization of a Novel Botulinum Neurotoxin Type H Gene Dover, Nir; Barash, Jason R.; Hill, Karen K. The Journal of Infectious Diseases, Vol. 209, Issue 2 https://doi.org/10.1093/infdis/jit450	journal	October 2013
Identification of the synaptic vesicle glycoprotein 2 receptor binding site in botulinum neurotoxin A Strotmeier, Jasmin; Mahrhold, Stefan; Krez, Nadja FEBS Letters, Vol. 588, Issue 7 https://doi.org/10.1016/j.febslet.2014.02.034	journal	February 2014
Fast, scalable generation of high‐quality protein multiple sequence alignments using Clustal Omega Sievers, Fabian; Wilm, Andreas; Dineen, David Molecular Systems Biology, Vol. 7, Issue 1 https://doi.org/10.1038/msb.2011.75	journal	January 2011
Crystal Structures of Botulinum Neurotoxin DC in Complex with Its Protein Receptors Synaptotagmin I and II Berntsson, Ronnie Per-Arne; Peng, Lisheng; Svensson, Linda Marie Structure, Vol. 21, Issue 9 https://doi.org/10.1016/j.str.2013.06.026	journal	September 2013
Two Cases of Type E Infant Botulism Caused by Neurotoxigenic Clostridium butyricum in Italy Aureli, P.; Fenicia, L.; Pasolini, B. Journal of Infectious Diseases, Vol. 154, Issue 2 https://doi.org/10.1093/infdis/154.2.207	journal	August 1986
Botulinum neurotoxins: genetic, structural and mechanistic insights Rossetto, Ornella; Pirazzini, Marco; Montecucco, Cesare Nature Reviews Microbiology, Vol. 12, Issue 8 https://doi.org/10.1038/nrmicro3295	journal	June 2014
Molecular evolution of antibody cross-reactivity for two subtypes of type A botulinum neurotoxin Garcia-Rodriguez, Consuelo; Levy, Raphael; Arndt, Joseph W. Nature Biotechnology, Vol. 25, Issue 1 https://doi.org/10.1038/nbt1269	journal	December 2006
SV2C is a synaptic vesicle protein with an unusually restricted localization: anatomy of a synaptic vesicle protein family Janz, R.; Südhof, T. C. Neuroscience, Vol. 94, Issue 4 https://doi.org/10.1016/S0306-4522(99)00370-X	journal	November 1999
Molecular basis for disruption of E-cadherin adhesion by botulinum neurotoxin A complex Lee, K.; Zhong, X.; Gu, S. Science, Vol. 344, Issue 6190 https://doi.org/10.1126/science.1253823	journal	June 2014
Phaser crystallographic software McCoy, Airlie J.; Grosse-Kunstleve, Ralf W.; Adams, Paul D. Journal of Applied Crystallography, Vol. 40, Issue 4 https://doi.org/10.1107/s0021889807021206	journal	July 2007
Cleavage of members of the synaptobrevin/VAMP family by types D and F botulinal neurotoxins and tetanus toxin. Yamasaki, S.; Baumeister, A.; Binz, T. Journal of Biological Chemistry, Vol. 269, Issue 17 https://doi.org/10.1016/S0021-9258(18)99941-2	journal	April 1994
Phylogeny and taxonomy of the food-borne pathogen Clostridium botulinum and its neurotoxins No authors listed Journal of Applied Microbiology, Vol. 84, Issue 1 https://doi.org/10.1046/j.1365-2672.1997.00313.x	journal	January 1998
Botulinum Neurotoxin Is Shielded by NTNHA in an Interlocked Complex Gu, S.; Rumpel, S.; Zhou, J. Science, Vol. 335, Issue 6071 https://doi.org/10.1126/science.1214270	journal	February 2012
N-linked glycosylation of SV2 is required for binding and uptake of botulinum neurotoxin A Yao, Guorui; Zhang, Sicai; Mahrhold, Stefan Nature Structural & Molecular Biology, Vol. 23, Issue 7 https://doi.org/10.1038/nsmb.3245	journal	June 2016
MolProbity : all-atom structure validation for macromolecular crystallography Chen, Vincent B.; Arendall, W. Bryan; Headd, Jeffrey J. Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 1 https://doi.org/10.1107/S0907444909042073	journal	December 2009
Phaser crystallographic software McCoy, Airlie J.; Grosse-Kunstleve, Ralf W.; Adams, Paul D. Journal of Applied Crystallography, Vol. 40, Issue 4 https://doi.org/10.1107/S0021889807021206	journal	July 2007
Novel Application of Human Neurons Derived from Induced Pluripotent Stem Cells for Highly Sensitive Botulinum Neurotoxin Detection Whitemarsh, Regina C. M.; Strathman, Monica J.; Chase, Lucas G. Toxicological Sciences, Vol. 126, Issue 2 https://doi.org/10.1093/toxsci/kfr354	journal	January 2012
A graphical user interface to the CCP 4 program suite Potterton, Elizabeth; Briggs, Peter; Turkenburg, Maria Acta Crystallographica Section D Biological Crystallography, Vol. 59, Issue 7 https://doi.org/10.1107/S0907444903008126	journal	June 2003
Draft Genome Sequence of Bivalent Clostridium botulinum Strain IBCA10-7060, Encoding Botulinum Neurotoxin B and a New FA Mosaic Type Gonzalez-Escalona, N.; Thirunavukkarasu, N.; Singh, A. Genome Announcements, Vol. 2, Issue 6 https://doi.org/10.1128/genomeA.01275-14	journal	November 2014
Structural basis for recognition of synaptic vesicle protein 2C by botulinum neurotoxin A Benoit, Roger M.; Frey, Daniel; Hilbert, Manuel Nature, Vol. 505, Issue 7481 https://doi.org/10.1038/nature12732	journal	November 2013
Mosaic structures of neurotoxins produced from Clostridium botulinum types C and D organisms Moriishi, Kohji; Koura, Minako; Abe, Norio Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression, Vol. 1307, Issue 2 https://doi.org/10.1016/0167-4781(96)00006-1	journal	June 1996
Expression of SV2 isoforms during rodent brain development Crèvecœur, Julie; Foerch, Patrik; Doupagne, Melissa BMC Neuroscience, Vol. 14, Issue 1 https://doi.org/10.1186/1471-2202-14-87	journal	January 2013
MolProbity : all-atom structure validation for macromolecular crystallography Chen, Vincent B.; Arendall, W. Bryan; Headd, Jeffrey J. Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 1 https://doi.org/10.1107/s0907444909042073	journal	December 2009
Botulinum neurotoxin D-C uses synaptotagmin I and II as receptors, and human synaptotagmin II is not an effective receptor for type B, D-C and G toxins Peng, Lisheng; Berntsson, Ronnie P. -A; Tepp, William H. Journal of Cell Science, Vol. 125, Issue 13 https://doi.org/10.1242/jcs.103564	journal	March 2012
Purification and Characterization of Botulinum Neurotoxin FA from a Genetically Modified Clostridium botulinum Strain Pellett, Sabine; Tepp, William H.; Bradshaw, Marite mSphere, Vol. 1, Issue 1 https://doi.org/10.1128/msphere.00100-15	journal	February 2016
Botulinum neurotoxin A selectively cleaves the synaptic protein SNAP-25 Blasi, Juan; Chapman, Edwin R.; Link, Egenhard Nature, Vol. 365, Issue 6442 https://doi.org/10.1038/365160a0	journal	September 1993
Historical Perspectives and Guidelines for Botulinum Neurotoxin Subtype Nomenclature Peck, Michael; Smith, Theresa; Anniballi, Fabrizio Toxins, Vol. 9, Issue 1 https://doi.org/10.3390/toxins9010038	journal	January 2017
High-resolution crystal structure of HA33 of botulinum neurotoxin type B progenitor toxin complex Lee, Kwangkook; Lam, Kwok-Ho; Kruel, Anna Magdalena Biochemical and Biophysical Research Communications, Vol. 446, Issue 2 https://doi.org/10.1016/j.bbrc.2014.03.008	journal	April 2014
Fine and Domain-level Epitope Mapping of Botulinum Neurotoxin Type A Neutralizing Antibodies by Yeast Surface Display Levy, R.; Forsyth, C. M.; LaPorte, S. L. Journal of Molecular Biology, Vol. 365, Issue 1 https://doi.org/10.1016/j.jmb.2006.09.084	journal	January 2007
Two Feet on the Membrane: Uptake of Clostridial Neurotoxins Rummel, Andreas Current Topics in Microbiology and Immunology https://doi.org/10.1007/82_2016_48	book	January 2016
A graphical user interface to the CCP 4 program suite Potterton, Elizabeth; Briggs, Peter; Turkenburg, Maria Acta Crystallographica Section D Biological Crystallography, Vol. 59, Issue 7 https://doi.org/10.1107/s0907444903008126	journal	June 2003
Host ANP32A mediates the assembly of the influenza virus replicase Carrique, Loïc; Fan, Haitian; Walker, Alexander P. Nature, Vol. 587, Issue 7835 https://doi.org/10.1038/s41586-020-2927-z	journal	November 2020
SV2C is a synaptic vesicle protein with an unusually restricted localization: anatomy of a synaptic vesicle protein family Janz, R.; Südhof, T. C. Neuroscience, Vol. 94, Issue 4 https://doi.org/10.1016/s0306-4522(99)00370-x	journal	November 1999
iMOSFLM : a new graphical interface for diffraction-image processing with MOSFLM Battye, T. Geoff G.; Kontogiannis, Luke; Johnson, Owen Acta Crystallographica Section D Biological Crystallography, Vol. 67, Issue 4 https://doi.org/10.1107/s0907444910048675	journal	March 2011
Distribution of SV2C mRNA and protein expression in the mouse brain with a particular emphasis on the basal ganglia system Dardou, D.; Dassesse, D.; Cuvelier, L. Brain Research, Vol. 1367 https://doi.org/10.1016/j.brainres.2010.09.063	journal	January 2011
iMOSFLM : a new graphical interface for diffraction-image processing with MOSFLM Battye, T. Geoff G.; Kontogiannis, Luke; Johnson, Owen Acta Crystallographica Section D Biological Crystallography, Vol. 67, Issue 4 https://doi.org/10.1107/S0907444910048675	journal	March 2011
Tetanus and botulinum-B neurotoxins block neurotransmitter release by proteolytic cleavage of synaptobrevin Schiavo, Giampietro G.; Benfenati, Fabio; Poulain, Bernard Nature, Vol. 359, Issue 6398 https://doi.org/10.1038/359832a0	journal	October 1992
Safety and Pharmacokinetics of XOMA 3AB, a Novel Mixture of Three Monoclonal Antibodies against Botulinum Toxin A Nayak, S. U.; Griffiss, J. M.; McKenzie, R. Antimicrobial Agents and Chemotherapy, Vol. 58, Issue 9 https://doi.org/10.1128/aac.02830-14	journal	June 2014
Safety and Pharmacokinetics of XOMA 3AB, a Novel Mixture of Three Monoclonal Antibodies against Botulinum Toxin A Nayak, S. U.; Griffiss, J. M.; McKenzie, R. Antimicrobial Agents and Chemotherapy, Vol. 58, Issue 9 https://doi.org/10.1128/AAC.02830-14	journal	June 2014
Coot model-building tools for molecular graphics Emsley, Paul; Cowtan, Kevin Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 12, p. 2126-2132 https://doi.org/10.1107/S0907444904019158	journal	November 2004
Isolation and Functional Characterization of the Novel Clostridium botulinum Neurotoxin A8 Subtype Kull, Skadi; Schulz, K. Melanie; Strotmeier, Jasmin Weisemann née PLOS ONE, Vol. 10, Issue 2 https://doi.org/10.1371/journal.pone.0116381	journal	February 2015
How do tetanus and botulinum toxins bind to neuronal membranes? Montecucco, Cesare Trends in Biochemical Sciences, Vol. 11, Issue 8 https://doi.org/10.1016/0968-0004(86)90282-3	journal	August 1986
Assembly and Function of the Botulinum Neurotoxin Progenitor Complex Gu, Shenyan; Jin, Rongsheng Botulinum Neurotoxins https://doi.org/10.1007/978-3-662-45790-0_2	book	January 2012
Deciphering key features in protein structures with the new ENDscript server Robert, Xavier; Gouet, Patrice Nucleic Acids Research, Vol. 42, Issue W1 https://doi.org/10.1093/nar/gku316	journal	April 2014
Botulism Johnson, Eric A.; Montecucco, Cesare Handbook of Clinical Neurology https://doi.org/10.1016/S0072-9752(07)01511-4	book	January 2008
Identification of the protein receptor binding site of botulinum neurotoxins B and G proves the double-receptor concept Rummel, A.; Eichner, T.; Weil, T. Proceedings of the National Academy of Sciences, Vol. 104, Issue 1 https://doi.org/10.1073/pnas.0609713104	journal	December 2006
Botulinum Toxin as a Biological Weapon: Medical and Public Health Management Arnon, Stephen S.; Schechter, Robert; Inglesby, Thomas V. JAMA, Vol. 285, Issue 8 https://doi.org/10.1001/jama.285.8.1059	journal	February 2001
Medical aspects of toxin weapons Bigalke, Hans; Rummel, Andreas Toxicology, Vol. 214, Issue 3 https://doi.org/10.1016/j.tox.2005.06.015	journal	October 2005
Historical Perspectives and Guidelines for Botulinum Neurotoxin Subtype Nomenclature Peck, Michael W.; Smith, Theresa J.; Anniballi, Fabrizio Robert Koch-Institut, Biologische Sicherheit https://doi.org/10.25646/2465	other	January 2017
Coot model-building tools for molecular graphics Emsley, Paul; Cowtan, Kevin Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 12, p. 2126-2132 https://doi.org/10.1107/s0907444904019158	journal	November 2004
Immunological Characterization and Neutralizing Ability of Monoclonal Antibodies Directed Against Botulinum Neurotoxin Type H Fan, Yongfeng; Barash, Jason R.; Lou, Jianlong Journal of Infectious Diseases, Vol. 213, Issue 10 https://doi.org/10.1093/infdis/jiv770	journal	March 2016
Discovery of a novel enzymatic cleavage site for botulinum neurotoxin F5 Kalb, Suzanne R.; Baudys, Jakub; Webb, Robert P. FEBS Letters, Vol. 586, Issue 2 https://doi.org/10.1016/j.febslet.2011.11.033	journal	December 2011
Quantum dot immunoassays in renewable surface column and 96-well plate formats for the fluorescence detection of botulinum neurotoxin using high-affinity antibodies Warner, Marvin G.; Grate, Jay W.; Tyler, Abby Biosensors and Bioelectronics, Vol. 25, Issue 1 https://doi.org/10.1016/j.bios.2009.06.031	journal	September 2009
A Novel Botulinum Neurotoxin, Previously Reported as Serotype H, Has a Hybrid-Like Structure With Regions of Similarity to the Structures of Serotypes A and F and Is Neutralized With Serotype A Antitoxin Maslanka, Susan E.; Lúquez, Carolina; Dykes, Janet K. Journal of Infectious Diseases, Vol. 213, Issue 3 https://doi.org/10.1093/infdis/jiv327	journal	June 2015

Cited By (6)

The Novel Clostridial Neurotoxin Produced by Strain IBCA10-7060 Is Immunologically Equivalent to BoNT/HA Fan, Yongfeng; Barash, Jason R.; Conrad, Fraser Toxins, Vol. 12, Issue 1 https://doi.org/10.3390/toxins12010009	journal	December 2019
A Three Monoclonal Antibody Combination Potently Neutralizes Multiple Botulinum Neurotoxin Serotype E Subtypes Garcia-Rodriguez, Consuelo; Razai, Ali; Geren, Isin Toxins, Vol. 10, Issue 3 https://doi.org/10.3390/toxins10030105	journal	March 2018
Novel Botulinum Neurotoxins: Exploring Underneath the Iceberg Tip Tehran, Domenico; Pirazzini, Marco Toxins, Vol. 10, Issue 5 https://doi.org/10.3390/toxins10050190	journal	May 2018
Botulinum toxin: State of the art: Botulinum Toxin Jankovic, Joseph Movement Disorders, Vol. 32, Issue 8 https://doi.org/10.1002/mds.27072	journal	June 2017
High resolution crystal structures of the receptor-binding domain ofClostridium botulinumneurotoxin serotypes A and FA Davies, Jonathan R.; Hackett, Gavin S.; Liu, Sai Man PeerJ, Vol. 6 https://doi.org/10.7717/peerj.4552	journal	March 2018
Purification and Characterization of Recombinant Botulinum Neurotoxin Serotype FA, Also Known as Serotype H Hackett, Gavin; Moore, Kevin; Burgin, David Toxins, Vol. 10, Issue 5 https://doi.org/10.3390/toxins10050195	journal	May 2018

Similar Records

Crystal structure of the receptor-binding domain of botulinum neurotoxin type HA, also known as type FA or H

Journal Article · Tue Mar 07 19:00:00 EST 2017 · Toxins · OSTI ID:1355928

A camelid single-domain antibody neutralizes botulinum neurotoxin A by blocking host receptor binding

Journal Article · Mon Aug 07 00:00:00 EDT 2017 · Scientific Reports · OSTI ID:1379429

Structure Based Discovery of Pan Active Botulinum Neurotoxin Inhibitors

Journal Article · Tue Feb 13 19:00:00 EST 2018 · Structure Based Discovery of Pan Active Botulinum Neurotoxin Inhibitors · OSTI ID:1425108

Related Subjects

60 APPLIED LIFE SCIENCES

Crystal Structure of the Receptor-Binding Domain of Botulinum Neurotoxin Type HA, Also Known as Type FA or H

Citation Formats

References (58)

Cited By (6)

Similar Records

Related Subjects