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

• Crystallographic study reveals the three-dimensional structure of LBP
• Structural differences from BPI are key for LBP’s distinct function
• A frequently occurring human LBP mutation strongly alters LBP function
• Structural integrity of LBP is key for the course of infectious diseases in patients

SummaryLipopolysaccharide (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 2.9 Å 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 (allelic frequency 0.08) affected this region, potentially generating a proteinase cleavage site. The mutant protein had a reduced binding capacity for LPS and lipopeptides. SNP carriers displayed a reduced cytokine response after in vivo 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 structural integrity of LBP may be crucial for fighting infections efficiently, and future patient stratification might help to develop better therapeutic strategies.