# Lpt protein-mediated transport of LPS

> **NIH NIH R01** · MEDICAL COLLEGE OF WISCONSIN · 2020 · $354,200

## Abstract

Project Summary
 Lipopolysaccharide (LPS) is the major component of the outer leaflet of the outer membrane (OM) of Gram-
negative bacteria such as Escherichia coli, Salmonella typhimurium and many other important pathogens. LPS
(or endotoxin) is essential for survival in this large class of bacteria and serves as a first line of defense against
hostile environments encountered during host infection. Given the essential role of LPS in the survival of Gram-
negative bacteria – i.e., the bacterial cells die if any step of LPS transport does not occur – and the unique cell
surface it creates, a detailed understanding of the proteins and mechanisms involved in LPS synthesis and
transport will be the foundation on which to develop novel antibiotics against these promising new drug targets.
 Seven proteins make up the LPS transport (Lpt) system: the inner membrane (IM) ABC transporter LptB2FG,
the membrane-anchored periplasmic protein LptC, the periplasmic protein LptA, which is speculated to form a
bridge between LptC and LptD to protect the hydrophobic acyl chains of LPS during transport through the
periplasm, and the OM protein complex LptDE that inserts LPS into the outer leaflet of the OM. In an exciting
advance, the structures of all seven proteins in the Lpt system involved in LPS transport have now been solved.
Strikingly, the five periplasmic domains of the Lpt system show remarkable structural homology and the crystal
structures provide valuable insights into the mechanism of the essential LPS transport process, yet it is still
unknown how LPS is transported across the putative periplasmic Lpt bridge of Gram-negative bacteria. Great
progress has been made, including identifying the key players in LPS transport, determining the crystal structures
for each of the Lpt proteins, developing the bridge model, and identifying and quantitating the LPS binding site
on LptA and LptC, and yet many questions remain regarding the mechanism of transport of such a critical
molecule in Gram-negative bacterial physiology. The hypothesis that unfolding/folding events occur in the
periplasmic Lpt proteins to move LPS along the periplasmic bridge and that removal of amino acid side chains
critical to the stabilization of the protein-protein and protein-lipid interactions will disrupt LPS transport in vivo will
be tested through a combination of complementary biophysical techniques, computational studies and in vivo
assays. The successful completion of the proposed aims will include the identification and quantitation of the
interaction interfaces of the periplasmic bridge assembly for LPS transport in Gram-negative bacteria and the
mechanism and quantitation of LPS binding to each periplasmic domain in the Lpt system to yield important
insights into the essential LPS transport process in bacteria. The long-term goal of this research is to understand
the protein-protein and protein-ligand interactions involved in LPS transport to enable the effective design of
no...

## Key facts

- **NIH application ID:** 10016341
- **Project number:** 5R01GM108817-06
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** CANDICE S KLUG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $354,200
- **Award type:** 5
- **Project period:** 2014-09-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10016341

## Citation

> US National Institutes of Health, RePORTER application 10016341, Lpt protein-mediated transport of LPS (5R01GM108817-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10016341. Licensed CC0.

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