| Structural highlights
Disease
[HEP2_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]
Function
[HEP2_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 PubMed
The 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
- ↑ Blinder MA, Andersson TR, Abildgaard U, Tollefsen DM. Heparin cofactor IIOslo. Mutation of Arg-189 to His decreases the affinity for dermatan sulfate. J Biol Chem. 1989 Mar 25;264(9):5128-33. PMID:2647747
- ↑ Cargill M, Altshuler D, Ireland J, Sklar P, Ardlie K, Patil N, Shaw N, Lane CR, Lim EP, Kalyanaraman N, Nemesh J, Ziaugra L, Friedland L, Rolfe A, Warrington J, Lipshutz R, Daley GQ, Lander ES. Characterization of single-nucleotide polymorphisms in coding regions of human genes. Nat Genet. 1999 Jul;22(3):231-8. PMID:10391209 doi:10.1038/10290
- ↑ Kanagawa Y, Shigekiyo T, Aihara K, Akaike M, Azuma H, Matsumoto T. Molecular mechanism of type I congenital heparin cofactor (HC) II deficiency caused by a missense mutation at reactive P2 site: HC II Tokushima. Thromb Haemost. 2001 Jan;85(1):101-7. PMID:11204559
- ↑ Corral J, Aznar J, Gonzalez-Conejero R, Villa P, Minano A, Vaya A, Carrell RW, Huntington JA, Vicente V. Homozygous deficiency of heparin cofactor II: relevance of P17 glutamate residue in serpins, relationship with conformational diseases, and role in thrombosis. Circulation. 2004 Sep 7;110(10):1303-7. Epub 2004 Aug 30. PMID:15337701 doi:10.1161/01.CIR.0000140763.51679.D9
- ↑ Van Deerlin VM, Tollefsen DM. The N-terminal acidic domain of heparin cofactor II mediates the inhibition of alpha-thrombin in the presence of glycosaminoglycans. J Biol Chem. 1991 Oct 25;266(30):20223-31. PMID:1939083
- ↑ Van Deerlin VM, Tollefsen DM. The N-terminal acidic domain of heparin cofactor II mediates the inhibition of alpha-thrombin in the presence of glycosaminoglycans. J Biol Chem. 1991 Oct 25;266(30):20223-31. PMID:1939083
- ↑ Singh S, Datta A, Schmidtchen A, Bhunia A, Malmsten M. Tryptophan end-tagging for promoted lipopolysaccharide interactions and anti-inflammatory effects. Sci Rep. 2017 Mar 16;7(1):212. doi: 10.1038/s41598-017-00188-7. PMID:28303012 doi:http://dx.doi.org/10.1038/s41598-017-00188-7
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