Widespread Sequence Variations in VAMP1 across Vertebrates Suggest a Potential Selective Pressure from Botulinum Neurotoxins

PLoS Pathogens

Eric A. Johnson¹  William H. Tepp¹  Min Dong²  Liang Tao²  Lisheng Peng²  Ann Demogines³  Sara L. Sawyer³  Andrew Borrell⁴  Michael Adler⁴  Huisheng Liu⁵  Su-Chun Zhang⁵ 

[1] Department of Bacteriology, University of Wisconsin, Madison, Wisconsin, United States of America;Department of Microbiology and Immunobiology, Harvard Medical School and Division of Neuroscience, New England Primate Research Center, Southborough, Massachusetts, United States of America;Department of Molecular Biosciences, University of Texas, Austin, Texas, United States of America;Neurobehavioral Toxicology Branch, U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Aberdeen, Maryland, United States of America;Waisman Center, Department of Neuroscience, Department of Neurology, University of Wisconsin, Madison, Wisconsin, United States of America

关键词: Thoracic diaphragm;    Primates;    Motor neurons;    Neurons;    Toxins;    Botulinum toxin;    Immunostaining;    Membrane proteins;   

DOI  :  10.1371/journal.ppat.1004177

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Botulinum neurotoxins (BoNT/A-G), the most potent toxins known, act by cleaving three SNARE proteins required for synaptic vesicle exocytosis. Previous studies on BoNTs have generally utilized the major SNARE homologues expressed in brain (VAMP2, syntaxin 1, and SNAP-25). However, BoNTs target peripheral motor neurons and cause death by paralyzing respiratory muscles such as the diaphragm. Here we report that VAMP1, but not VAMP2, is the SNARE homologue predominantly expressed in adult rodent diaphragm motor nerve terminals and in differentiated human motor neurons. In contrast to the highly conserved VAMP2, BoNT-resistant variations in VAMP1 are widespread across vertebrates. In particular, we identified a polymorphism at position 48 of VAMP1 in rats, which renders VAMP1 either resistant (I48) or sensitive (M48) to BoNT/D. Taking advantage of this finding, we showed that rat diaphragms with I48 in VAMP1 are insensitive to BoNT/D compared to rat diaphragms with M48 in VAMP1. This unique intra-species comparison establishes VAMP1 as a physiological toxin target in diaphragm motor nerve terminals, and demonstrates that the resistance of VAMP1 to BoNTs can underlie the insensitivity of a species to members of BoNTs. Consistently, human VAMP1 contains I48, which may explain why humans are insensitive to BoNT/D. Finally, we report that residue 48 of VAMP1 varies frequently between M and I across seventeen closely related primate species, suggesting a potential selective pressure from members of BoNTs for resistance in vertebrates.

【 授权许可】

CC BY