Botulinum Neurotoxin A4 Has a 1000-Fold Reduced Potency Due to Three Single Amino Acid Alterations in the Protein Receptor Binding Domain.

ABSTRACT: Botulinum neurotoxin subtype A4 (BoNT/A4) is ~1000-fold less potent than BoNT/A1. This study addresses the basis for low BoNT/A4 potency. Utilizing BoNT/A1-A4 and BoNT/A4-A1 Light Chain-Heavy Chain (LC-HC) chimeras, HC-A4 was responsible for low BoNT/A4 potency. Earlier studies showed BoNT/A1-receptor binding domain (Hcc) bound a β-strand peptide (556-564) and glycan-N⁵⁵⁹ within Luminal Domain 4 (LD4) of SV2C, the BoNT/A protein receptor. Relative to BoNT/A1, the Hcc of BoNT/A4 possesses two amino acid variants (D¹¹⁴¹ and N¹¹⁴²) within the β-peptide binding interface and one amino acid variant (R¹²⁹²) located near the SV2C glycan-N⁵⁵⁹. Introduction of BoNT/A4 β-strand peptide variant (D¹¹⁴¹ and N¹¹⁴²) into BoNT/A1

SUBMITTER: Tepp WH 

PROVIDER: S-EPMC10055998 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature