The crystal structure of lipopolysaccharide binding protein reveals the location of a frequent mutation that impairs innate immunity

Jana K Eckert; Young J Kim; Jung I Kim; Kathleen Gürtler; Djin-Ye Oh; Saubashya Sur; Linn Lundvall; Lutz Hamann; Anke van der Ploeg; Peter Pickkers; Evangelos Giamarellos-Bourboulis; Andriy V Kubarenko; Alexander N Weber; Michael Kabesch; Oliver Kumpf; Hyun-Jung An; Jie-Oh Lee; Ralf R Schumann

doi:10.1016/j.immuni.2013.09.005

The crystal structure of lipopolysaccharide binding protein reveals the location of a frequent mutation that impairs innate immunity

Immunity. 2013 Oct 17;39(4):647-60. doi: 10.1016/j.immuni.2013.09.005. Epub 2013 Oct 10.

Authors

Jana K Eckert¹, Young J Kim, Jung I Kim, Kathleen Gürtler, Djin-Ye Oh, Saubashya Sur, Linn Lundvall, Lutz Hamann, Anke van der Ploeg, Peter Pickkers, Evangelos Giamarellos-Bourboulis, Andriy V Kubarenko, Alexander N Weber, Michael Kabesch, Oliver Kumpf, Hyun-Jung An, Jie-Oh Lee, Ralf R Schumann

Affiliation

¹ Institute for Microbiology and Hygiene, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany.

PMID: 24120359
DOI: 10.1016/j.immuni.2013.09.005

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 2.9 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acute-Phase Proteins / chemistry*
Acute-Phase Proteins / genetics
Acute-Phase Proteins / immunology
Animals
Antimicrobial Cationic Peptides / chemistry*
Antimicrobial Cationic Peptides / genetics
Antimicrobial Cationic Peptides / immunology
Binding Sites
Blood Proteins / chemistry*
Blood Proteins / genetics
Blood Proteins / immunology
Carrier Proteins / chemistry*
Carrier Proteins / genetics
Carrier Proteins / immunology
Crystallography, X-Ray
Genotype
Humans
Hydrophobic and Hydrophilic Interactions
Immunity, Innate / genetics*
Lipopolysaccharides / chemistry*
Lipopolysaccharides / immunology
Membrane Glycoproteins / chemistry*
Membrane Glycoproteins / genetics
Membrane Glycoproteins / immunology
Mice
Models, Molecular*
Mutation*
Polymorphism, Single Nucleotide*
Protein Binding
Protein Structure, Tertiary
Static Electricity
Structural Homology, Protein

Substances

Acute-Phase Proteins
Antimicrobial Cationic Peptides
Blood Proteins
Carrier Proteins
Lipopolysaccharides
Membrane Glycoproteins
bactericidal permeability increasing protein
lipopolysaccharide-binding protein