# Structural basis for recognition of SV2 by type E botulinum neurotoxin

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA-IRVINE · 2022 · $196,250

## Abstract

Abstract
Botulinum neurotoxins (BoNTs) are produced by the bacterium Clostridium botulinum, which are the causative
agents of neuroparalytic disease botulism. Nevertheless, type A and type B botulinum neurotoxins (BoNT/A and
BoNT/B) have been successfully used in clinic for a variety of aesthetic and therapeutic applications. The high
potency of BoNTs relies on the specific and efficient binding and uptake of BoNTs by motor neurons at
neuromuscular junctions. Inside the neurons, BoNTs cleave SNARE complex and block the release of
acetylcholine, resulting in paralysis of the affected muscles. It is well accepted that most BoNTs synergistically
bind specific protein receptors and gangliosides on motor neurons for cell entry. Remarkably, BoNTs develop
diverse binding modes for protein receptor recognition, in contrast to a conserved ganglioside-binding mode. In
this study, we will focus on the type E toxin (BoNT/E) that is the least studied human pathogenic BoNT in
comparison to well-characterized BoNT/A and BoNT/B. Paradoxically, BoNT/E is currently in clinic trial as a new
therapeutic and aesthetic product, which displays distinct pharmacological and clinic features when compared
to BoNT/A and BoNT/B. At the molecular level, BoNT/E recognizes two of the three isoforms of synaptic vesicle
glycoprotein 2 (SV2A and SV2B) as its neuronal receptors for cell entry, but not the closely related SV2C isoform.
As SV2A, 2B, and 2C have different tissue distribution in vivo, a better understanding of how BoNT/E recognizes
SV2A, 2B, and 2C differentially is crucial to understand the therapeutic profiles of BoNT/E-based drugs as well
as to develop new indications. To this end, we propose two Specific Aims using an integrated approach that
combines X-ray crystallography, site-directed mutagenesis, and binding assays. In Aim 1, we propose to study
the structural basis for recognition of SV2A by BoNT/E. In Aim 2, we aim to understand the affinity and specificity
requirements for BoNT/E to recognize three SV2 isoforms, while all the structural findings will be verified by
structure-based mutagenesis studies. The achievement of our goals will help to understand the unique
pharmacological and clinical profiles of BoNT/E, as well as to facilitate the design of new countermeasures
against BoNT/E.

## Key facts

- **NIH application ID:** 10448471
- **Project number:** 5R21AI163178-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Rongsheng Jin
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $196,250
- **Award type:** 5
- **Project period:** 2021-07-09 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10448471

## Citation

> US National Institutes of Health, RePORTER application 10448471, Structural basis for recognition of SV2 by type E botulinum neurotoxin (5R21AI163178-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10448471. Licensed CC0.

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