The Crystal Structure of Lipopolysaccharide Binding Protein Reveals the Location of a Frequent Mutation that Impairs Innate Immunity

Abstract

Lipopolysaccharide (LPS) binding protein (LBP) is an acute-phase protein that initiates an immune response after recognition of bacterial LPS. Here, we report the crystal structure of murine LBP at 2.9Å resolution. Several structural differences were observed between LBP and the related bactericidal/permeability-increasing protein (BPI), and the LBP C-terminal domain contained a negatively charged groove and a hydrophobic "phenylalanine core." A frequent human LBP SNP (allelicfrequency 0.08) affected this region, potentially generating a proteinase cleavage site. The mutantprotein had a reduced binding capacity for LPS and lipopeptides. SNP carriers displayed a reducedcytokine response after invivo LPS exposure and lower cytokine concentrations in pneumonia. In a retrospective trial, the LBP SNP was associated with increased mortality rates during sepsis and pneumonia. Thus, the structuralintegrity of LBP may be crucial for fighting infections efficiently, and future patient stratificationmight help to develop better therapeutic strategies.