Open AccessDynamics of an LPS translocon induced by substrate and an antimicrobial peptide
Author(s) -
Francesco Fiorentino,
Joshua B. Sauer,
Xingyu Qiu,
Robin A. Corey,
C. Keith Cassidy,
Benjamin Mynors-Wallis,
Shahid Mehmood,
Jani Reddy Bolla,
Phillip J. Stansfeld,
Carol V. Robinson
Publication year - 2020
Publication title -
nature chemical biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.412
H-Index - 216
eISSN - 1552-4469
pISSN - 1552-4450
DOI - 10.1038/s41589-020-00694-2
Subject(s) - biogenesis , translocon , peptide , chemistry , molecular dynamics , biophysics , antimicrobial peptides , bacterial outer membrane , microbiology and biotechnology , biochemistry , biology , membrane , membrane protein , escherichia coli , computational chemistry , gene
Lipopolysaccharide (LPS) transport to the outer membrane (OM) is a crucial step in the biogenesis of microbial surface defenses. Although many features of the translocation mechanism have been elucidated, molecular details of LPS insertion via the LPS transport (Lpt) OM protein LptDE remain elusive. Here, we integrate native MS with hydrogen-deuterium exchange MS and molecular dynamics simulations to investigate the influence of substrate and peptide binding on the conformational dynamics of LptDE. Our data reveal that LPS induces opening of the LptD β-taco domain, coupled with conformational changes on β-strands adjacent to the putative lateral exit gate. Conversely, an antimicrobial peptide, thanatin, stabilizes the β-taco, thereby preventing LPS transport. Our results illustrate that LPS insertion into the OM relies on concerted opening movements of both the β-barrel and β-taco domains of LptD, and suggest a means for developing antimicrobial therapeutics targeting this essential process in Gram-negative ESKAPE pathogens.