2ncu
NMR structure of KYE21 in LPS micelles
Structural highlights
DiseaseHEP2_HUMAN Defects in SERPIND1 are the cause of thrombophilia due to heparin cofactor 2 deficiency (THPH10) [MIM:612356. A hemostatic disorder characterized by a tendency to recurrent thrombosis.[1] [2] [3] [4] FunctionHEP2_HUMAN Thrombin inhibitor activated by the glycosaminoglycans, heparin or dermatan sulfate. In the presence of the latter, HC-II becomes the predominant thrombin inhibitor in place of antithrombin III (AT-III). Also inhibits chymotrypsin, but in a glycosaminoglycan-independent manner.[5] Peptides at the N-terminal of HC-II have chemotactic activity for both monocytes and neutrophils.[6] Publication Abstract from PubMedThe objective of the present study is the investigation of possibilities for boosting peptide anti-inflammatory effects by tryptophan end-tagging, including identification of underlying mechanisms for this. In doing so, effects of tryptophan end-tagging of KYE21 (KYEITTIHNLFRKLTHRLFRR), a peptide derived from heparin co-factor II, on membrane and lipopolysaccharide (LPS) interactions were investigated by ellipsometry, NMR, fluorescence spectroscopy, and circular dichroism measurements. Through its N-terminal W stretch, WWWKYE21 displays higher membrane binding, liposome rupture, and bacterial killing than unmodified KYE21. Analogously, W-tagging promotes binding to E. coli LPS and to its endotoxic lipid A moiety. Furthermore, WWWKYE21 causes more stable peptide/LPS complexes than KYE21, as evidenced by detailed NMR studies, adopting a pronounced helical conformation, with a large hydrophobic surface at the N-terminus due to the presence of W-residues, and a flexible C-terminus due to presence of several positively charged arginine residues. Mirroring its increased affinity for LPS and lipid A, WWWKYE21 displays strongly increased anti-inflammatory effect due to a combination of direct lipid A binding, peptide-induced charge reversal of cell membranes for LPS scavenging, and peptide-induced fragmentation of LPS aggregates for improved phagocytosis. Importantly, potent anti-inflammatory effects were observed at low cell toxicity, demonstrated for both monocytes and erythrocytes. Tryptophan end-tagging for promoted lipopolysaccharide interactions and anti-inflammatory effects.,Singh S, Datta A, Schmidtchen A, Bhunia A, Malmsten M Sci Rep. 2017 Mar 16;7(1):212. doi: 10.1038/s41598-017-00188-7. PMID:28303012[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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