# Molecular Mechanisms of Lipopolysaccharide Transport Driven by ABC Transporters

> **NIH NIH R01** · HARVARD MEDICAL SCHOOL · 2020 · $339,000

## Abstract

ABSTRACT
Lipopolysaccharide (LPS) is present in the outer membrane of most Gram-negative bacteria, and plays
a key role in constructing a proper cellular envelope for bacteria to survive in harsh environments. The
tight packing of LPS in the outer membrane generates a network of charges and sugars, which selectively
allow the entry of nutrient molecules, while limit the penetration of toxic compounds including detergents
and antibiotics. Due to its critical importance in the biogenesis of bacterial membrane barrier, LPS
biosynthesis and transport pathway is a particularly interesting target for developing novel antibiotics.
LPS is also crucial in the host-pathogen interactions, and functions as a potent activator of innate immune
response in the animals. LPS is a complex and highly variable glycolipid, composed of a lipid A moiety,
a core oligosaccharide and a long-chain O-antigenic polysaccharide. The structure of lipid A and core
oligosaccharide are relatively conserved, presumably due to their roles in maintaining the integrity of
permeability barrier. In contrast, the O-antigen of LPS shows hypervariable structures, which is consistent
with their functions in interacting with the outside environment and host defense.
 Gram-negative bacteria devote a large amount of energy and a sophisticated protein machinery to the
efficient and proper production, transport and assembly of LPS molecules. The synthesis of LPS starts
at the interface between the cytoplasm and the inner membrane, leading to the generation of lipid A-core
oligosaccharide, also called rough LPS, which resides in the inner leaflet of the inner membrane. Rough
LPS is flipped across the inner membrane by an ATP binding cassette (ABC) transporter, MsbA. The
rough LPS in the periplasmic leaflet is further added with various lengths and forms of O-antigen,
becoming a “smooth” LPS. For the LPS transport across the periplasm and to the outer membrane, seven
proteins named as Lpt A-G are involved. Several lines of evidence converge to suggest a model, in which
the Lpt proteins form a continuous bridge connecting the two membranes. The ABC transporter, formed
as LptB2FG, is thought to extract the LPS molecules from the inner membrane, and transport them to the
tightly associated bitopic LptC, and to the periplasmic LptA. Multiple LptA proteins may form a continuous
bridge to reach the LptDE complex in the outer membrane, which mediates the LPS insertion into the
outer leaflet of the outer membrane. Here we propose a series of structural and functional studies on the
LPS transport protein machinery using a variety of biochemical and cryo-EM techniques. A molecular
understanding on the function and regulation of the LPS transport pathway will contribute to the
understanding of the biogenesis of the outer membrane of many Gram-negative bacteria, and also aid
the development of novel antibiotics that directly target the bacterial membrane barrier.

## Key facts

- **NIH application ID:** 9923673
- **Project number:** 5R01GM122797-04
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Maofu Liao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $339,000
- **Award type:** 5
- **Project period:** 2017-08-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9923673

## Citation

> US National Institutes of Health, RePORTER application 9923673, Molecular Mechanisms of Lipopolysaccharide Transport Driven by ABC Transporters (5R01GM122797-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9923673. Licensed CC0.

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