title: 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 2.9 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.
authors.affiliation: Institute for Microbiology and Hygiene, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany.
authors.forename: Jana K
authors.initials: JK
authors.lastname: Eckert
authors.forename: Young J
authors.initials: YJ
authors.lastname: Kim
authors.forename: Jung I
authors.initials: JI
authors.lastname: Kim
authors.forename: Kathleen
authors.initials: K
authors.lastname: Gürtler
authors.forename: Djin-Ye
authors.initials: DY
authors.lastname: Oh
authors.forename: Saubashya
authors.initials: S
authors.lastname: Sur
authors.forename: Linn
authors.initials: L
authors.lastname: Lundvall
authors.forename: Lutz
authors.initials: L
authors.lastname: Hamann
authors.forename: Anke
authors.initials: A
authors.lastname: van der Ploeg
authors.forename: Peter
authors.initials: P
authors.lastname: Pickkers
authors.forename: Evangelos
authors.initials: E
authors.lastname: Giamarellos-Bourboulis
authors.forename: Andriy V
authors.initials: AV
authors.lastname: Kubarenko
authors.forename: Alexander N
authors.initials: AN
authors.lastname: Weber
authors.forename: Michael
authors.initials: M
authors.lastname: Kabesch
authors.forename: Oliver
authors.initials: O
authors.lastname: Kumpf
authors.forename: Hyun-Jung
authors.initials: HJ
authors.lastname: An
authors.forename: Jie-Oh
authors.initials: JO
authors.lastname: Lee
authors.forename: Ralf R
authors.initials: RR
authors.lastname: Schumann
mesh_terms: D000209:Acute-Phase Proteins / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D001665:Binding Sites; D001798:Blood Proteins / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D002352:Carrier Proteins / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D018360:Crystallography, X-Ray; D005838:Genotype; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007113:Immunity, Innate / Q000235:genetics*; D008070:Lipopolysaccharides / Q000737:chemistry* / Q000276:immunology; D008562:Membrane Glycoproteins / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D051379:Mice; D008958:Models, Molecular; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D055672:Static Electricity; D040681:Structural Homology, Protein; D000099231:Lipopolysaccharide-Binding Protein
chemical_list: D000209:Acute-Phase Proteins; D023181:Antimicrobial Cationic Peptides; D001798:Blood Proteins; D002352:Carrier Proteins; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D000099231:Lipopolysaccharide-Binding Protein; C021623:bactericidal permeability increasing protein