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

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. Altogether, these new findings advance our understanding of the structure andmore » function of this newly identified toxin at the molecular level, and pave the way for the future development of more effective countermeasures.« less
Authors:
 [1] ;  [1] ;  [2] ;  [3] ; ORCiD logo [3] ;  [1]
  1. Univ. of California, Irvine, CA (United States)
  2. Argonne National Lab. (ANL), Argonne, IL (United States)
  3. Medizinische Hochschule Hannover, Hannover (Germany)
Publication Date:
Grant/Contract Number:
AC02-06CH11357
Type:
Accepted Manuscript
Journal Name:
Toxins
Additional Journal Information:
Journal Volume: 9; Journal Issue: 3; Journal ID: ISSN 2072-6651
Publisher:
MDPI
Research Org:
Univ. of California, Irvine, CA (United States)
Sponsoring Org:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; 59 BASIC BIOLOGICAL SCIENCES; botulinum neurotoxin (BoNT); BoNT/HA; BoNT/H; BoNT/FA; receptor-binding domain; host receptor; neutralizing antibody
OSTI Identifier:
1355928