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Crystal structure of the BoNT/A2 receptor-binding domain in complex with the luminal domain of its neuronal receptor SV2C.

Benoit RM, Schärer MA, Wieser MM, Li X, Frey D, Kammerer RA
Sci Rep 7 43588 (2017)
Cited: 17 times
EuropePMC logo PMID: 28252640

Abstract

A detailed molecular understanding of botulinum neurotoxin (BoNT)/host-cell-receptor interactions is fundamental both for developing strategies against botulism and for generating improved BoNT variants for medical applications. The X-ray crystal structure of the receptor-binding domain (HC) of BoNT/A1 in complex with the luminal domain (LD) of its neuronal receptor SV2C revealed only few specific side-chain - side-chain interactions that are important for binding. Notably, two BoNT/A1 residues, Arg 1156 and Arg 1294, that are crucial for the interaction with SV2, are not conserved among subtypes. Because it has been suggested that differential receptor binding of subtypes might explain their differences in biological activity, we determined the crystal structure of BoNT/A2-HC in complex with SV2C-LD. Although only few side-chain interactions are conserved between the two BoNT/A subtypes, the overall binding mode of subtypes A1 and A2 is virtually identical. In the BoNT/A2-HC - SV2C complex structure, a missing cation-π stacking is compensated for by an additional salt bridge and an anion-π stacking interaction, which explains why the binding of BoNT/A subtypes to SV2C tolerates variable side chains. These findings suggest that motif extensions and a shallow binding cleft in BoNT/A-HC contribute to binding specificity.

Reviews - 5moy mentioned but not cited (2)

  1. Current Understanding of the Structure and Function of Pentapeptide Repeat Proteins. Zhang R, Kennedy MA. Biomolecules 11 638 (2021)
  2. A Comprehensive Structural Analysis of Clostridium botulinum Neurotoxin A Cell-Binding Domain from Different Subtypes. Gregory KS, Acharya KR. Toxins (Basel) 15 92 (2023)

Articles - 5moy mentioned but not cited (4)

  1. Crystal structure of the BoNT/A2 receptor-binding domain in complex with the luminal domain of its neuronal receptor SV2C. Benoit RM, Schärer MA, Wieser MM, Li X, Frey D, Kammerer RA. Sci Rep 7 43588 (2017)
  2. A camelid single-domain antibody neutralizes botulinum neurotoxin A by blocking host receptor binding. Yao G, Lam KH, Weisemann J, Peng L, Krez N, Perry K, Shoemaker CB, Dong M, Rummel A, Jin R. Sci Rep 7 7438 (2017)
  3. Crystal Structure of Botulinum Neurotoxin A2 in Complex with the Human Protein Receptor SV2C Reveals Plasticity in Receptor Binding. Gustafsson R, Zhang S, Masuyer G, Dong M, Stenmark P. Toxins (Basel) 10 E153 (2018)
  4. Structural Features of Clostridium botulinum Neurotoxin Subtype A2 Cell Binding Domain. Gregory KS, Mahadeva TB, Liu SM, Acharya KR. Toxins (Basel) 14 356 (2022)


Reviews citing this publication (3)

  1. The Expanding Therapeutic Utility of Botulinum Neurotoxins. Fonfria E, Maignel J, Lezmi S, Martin V, Splevins A, Shubber S, Kalinichev M, Foster K, Picaut P, Krupp J. Toxins (Basel) 10 E208 (2018)
  2. Variations in the Botulinum Neurotoxin Binding Domain and the Potential for Novel Therapeutics. Davies JR, Liu SM, Acharya KR. Toxins (Basel) 10 E421 (2018)
  3. Critical Analysis of Neuronal Cell and the Mouse Bioassay for Detection of Botulinum Neurotoxins. Pellett S, Tepp WH, Johnson EA. Toxins (Basel) 11 E713 (2019)

Articles citing this publication (8)

  1. The Structure and Classification of Botulinum Toxins. Dong M, Stenmark P. Handb Exp Pharmacol 263 11-33 (2021)
  2. Botulinum neurotoxins A, B, C, E, and F preferentially enter cultured human motor neurons compared to other cultured human neuronal populations. Pellett S, Tepp WH, Johnson EA. FEBS Lett 593 2675-2685 (2019)
  3. Comparative functional analysis of mice after local injection with botulinum neurotoxin A1, A2, A6, and B1 by catwalk analysis. Moritz MS, Tepp WH, Inzalaco HN, Johnson EA, Pellett S. Toxicon 167 20-28 (2019)
  4. High-resolution crystal structures of the botulinum neurotoxin binding domains from subtypes A5 and A6. Davies JR, Britton A, Liu SM, Acharya KR. FEBS Open Bio 10 1474-1481 (2020)
  5. Knockin mouse models demonstrate differential contributions of synaptotagmin-1 and -2 as receptors for botulinum neurotoxins. Thaker H, Zhang J, Miyashita SI, Cristofaro V, Park S, Hashemi Gheinani A, Sullivan MP, Adam RM, Dong M. PLoS Pathog 17 e1009994 (2021)
  6. Botulinum Neurotoxin A4 Has a 1000-Fold Reduced Potency Due to Three Single Amino Acid Alterations in the Protein Receptor Binding Domain. Tepp WH, Bradshaw M, Gardner AP, Kaufman RL, Barbieri JT, Pellett S. Int J Mol Sci 24 5690 (2023)
  7. Structural basis for botulinum neurotoxin E recognition of synaptic vesicle protein 2. Liu Z, Lee PG, Krez N, Lam KH, Liu H, Przykopanski A, Chen P, Yao G, Zhang S, Tremblay JM, Perry K, Shoemaker CB, Rummel A, Dong M, Jin R. Nat Commun 14 2338 (2023)
  8. Split luciferase-based assay to detect botulinum neurotoxins using hiPSC-derived motor neurons. Cotter L, Yu F, Roqueviere S, Duchesne de Lamotte J, Krupp J, Dong M, Nicoleau C. Commun Biol 6 122 (2023)


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