| 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
KYE28 (KYEITTIHNLFRKLTHRLFRRNFGYT-LR), the representative sequence of helix D of heparin co-factor II, was demonstrated to be potent against agronomically important Gram-negative plant pathogens X. vesicatoria and X. oryzae, capable of inhibiting disease symptoms in detached tomato leaves. NMR studies in presence of lipopolysaccharide provided structural insights into the mechanisms underlying this, notably in relation to outer membrane permeabilisation. The three-dimensional solution structure of KYE28 in LPS is characterised by an N-terminal helical segment, an intermediate loop followed by another short helical stretch and an extended C-terminus. The two termini are in close proximity to each other via aromatic packing interactions, while the positively charged residues form an exterior polar shell. To further demonstrate the importance of the aromatic residues for this, a mutant peptide KYE28A, with Ala substitutions at F11, F19, F23 and Y25 was designed, that showed attenuated antimicrobial activity at high salt concentrations, as well as lower membrane disruption and LPS binding abilities compared to KYE28. In contrast to KYE28, KYE28A adopted an extended helical structure in LPS with extended N- and C-termini. Aromatic packing interactions were completely lost, although hydrophobic interaction between the side chains of hydrophobic residues were still partly retained, imparting an amphipathic character and explaining its residual antimicrobial activity and LPS binding as observed from ellipsometry and ITC. We thus present key structural aspects of KYE28, constituting an aromatic zipper, of potential importance for the development of novel plant protection agents and therapeutic agents.
Role of Aromatic Amino Acids in Lipopolysaccharide and Membrane Interactions of Antimicrobial Peptides for Use in Plant Disease Control.,Datta A, Bhattacharyya D, Singh S, Ghosh A, Schmidtchen A, Malmsten M, Bhunia A J Biol Chem. 2016 May 2. pii: jbc.M116.719575. PMID:27137928[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
- ↑ Datta A, Bhattacharyya D, Singh S, Ghosh A, Schmidtchen A, Malmsten M, Bhunia A. Role of Aromatic Amino Acids in Lipopolysaccharide and Membrane Interactions of Antimicrobial Peptides for Use in Plant Disease Control. J Biol Chem. 2016 May 2. pii: jbc.M116.719575. PMID:27137928 doi:http://dx.doi.org/10.1074/jbc.M116.719575
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