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 · Tue Mar 07 23:00:00 EST 2017 · Toxins

DOI:https://doi.org/10.3390/toxins9030093· OSTI ID:1355928

Yao, Guorui ^[1]; Lam, Kwok-ho ^[2]; Perry, Kay ^[3]; Weisemann, Jasmin ^[4]; ^[4]; Jin, Rongsheng ^[2]

Univ. of California, Irvine, CA (United States); University of California Irvine
Univ. of California, Irvine, CA (United States)
Argonne National Lab. (ANL), Argonne, IL (United States)
Medizinische Hochschule Hannover, Hannover (Germany)

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 and function of this newly identified toxin at the molecular level, and pave the way for the future development of more effective countermeasures.

View Accepted Manuscript (DOE)

Research Organization:: Univ. of California, Irvine, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1355928

Alternate ID(s):: OSTI ID: 1355042

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

Publisher:: MDPICopyright Statement

Country of Publication:: United States

Language:: English

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59 BASIC BIOLOGICAL SCIENCES
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receptor-binding domain

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

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Cited By (6)

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