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.
