1. Academic Validation
  2. Crystal structure of the mammalian lipopolysaccharide detoxifier

Crystal structure of the mammalian lipopolysaccharide detoxifier

  • Proc Natl Acad Sci U S A. 2018 Jan 30;115(5):E896-E905. doi: 10.1073/pnas.1719834115.
Alexei Gorelik 1 2 Katalin Illes 1 2 Bhushan Nagar 3 2
Affiliations

Affiliations

  • 1 Department of Biochemistry, McGill University, Montreal, H3G0B1, Canada.
  • 2 Groupe de Recherche Axé sur la Structure des Protéines, McGill University, Montreal, H3G0B1, Canada.
  • 3 Department of Biochemistry, McGill University, Montreal, H3G0B1, Canada; bhushan.nagar@mcgill.ca.
Abstract

LPS is a potent Bacterial endotoxin that triggers the innate immune system. Proper recognition of LPS by pattern-recognition receptors requires a full complement of typically six acyl chains in the lipid portion. Acyloxyacyl hydrolase (AOAH) is a host Enzyme that removes secondary (acyloxyacyl-linked) fatty acids from LPS, rendering it immunologically inert. This activity is critical for recovery from immune tolerance that follows Gram-negative Infection. To understand the molecular mechanism of AOAH function, we determined its crystal structure and its complex with LPS. The substrate's lipid moiety is accommodated in a large hydrophobic pocket formed by the saposin and catalytic domains with a secondary acyl chain inserted into a narrow lateral hydrophobic tunnel at the active site. The Enzyme establishes dispensable contacts with the phosphate groups of LPS but does not interact with its oligosaccharide portion. Proteolytic processing allows movement of an amphipathic helix possibly involved in substrate access at membranes.

Keywords

acyloxyacyl hydrolase; calcium-binding protein; immune tolerance; lipopolysaccharide; saposin.

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