Ederer, Katharina U. and Holzinger, Jonas M. and Maier, Katharina T. and Zeller, Lisa and Werner, Maren and Toelge, Martina and Gessner, Andre and Buelow, Sigrid (2022) A Polymorphism of Bactericidal/Permeability-Increasing Protein Affects Its Neutralization Efficiency towards Lipopolysaccharide. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 23 (3): 1324. ISSN , 1422-0067
Full text not available from this repository. (Request a copy)Abstract
Gram-negative sepsis driven by lipopolysaccharide (LPS) has detrimental outcomes, especially in neonates. The neutrophil-derived bactericidal/permeability-increasing protein (BPI) potently neutralizes LPS. Interestingly, polymorphism of the BPI gene at position 645 (rs4358188) corresponds to a favorable survival rate of these patients in the presence of at least one allele 645 A as opposed to 645 G. When we exploited the existing X-ray crystal structure, the corresponding amino acid at position 216 was revealed as surface exposed and proximal to the lipid-binding pocket in the N-terminal domain of BPI. Our further analysis predicted a shift in surface electrostatics by a positively charged lysine (BPI216K) exchanging a negatively charged glutamic acid (BPI216E). To investigate differences in interaction with LPS, we expressed both BPI variants recombinantly. The amino acid exchange neither affected affinity towards LPS nor altered bactericidal activity. However, when stimulating human peripheral blood mononuclear cells, BPI216K exhibited a superior LPS-neutralizing capacity (IC50 12.0 +/- 2.5 pM) as compared to BPI216E (IC50 152.9 +/- 113.4 pM, p = 0.0081) in respect to IL-6 secretion. In conclusion, we provide a functional correlate to a favorable outcome of sepsis in the presence of BPI216K.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | GRAM-NEGATIVE BACTERIA; N-TERMINAL FRAGMENT; VERSUS-HOST-DISEASE; CRYSTAL-STRUCTURE; BINDING PROTEIN; GENE VARIANTS; BPI; SEPSIS; RELEASE; DEFICIENT; bactericidal; permeability-increasing; lipopolysaccharide; sepsis; single nucleotide polymorphism |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Medizinische Mikrobiologie und Hygiene |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 09 Jan 2024 10:03 |
| Last Modified: | 09 Jan 2024 10:03 |
| URI: | https://pred.uni-regensburg.de/id/eprint/57116 |
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