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Alpha-1-proteinase inhibitor is a heparin binding serpin: Molecular interactions with the Lys rich cluster of helix-F domain.

Vivek Kumar, Gupta and Lalitha, R. Gowda (2008) Alpha-1-proteinase inhibitor is a heparin binding serpin: Molecular interactions with the Lys rich cluster of helix-F domain. Biochimie, 90 (5). 749-761 .

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Abstract

Alpha-1-proteinase (α-1-PI) inhibitor is the major circulating serine protease inhibitor in humans. The porcine elastase and trypsin inhibitory activity of human and ovine α-1-PI is activated several fold in the presence of anti-coagulant heparin. The activation is allosteric and appears to be characterized by two steps of binding; a weak followed by a strong binding. The Kass for ovine and human α-1-PI inhibition of porcine pancreatic elastase was increased 45 fold and 38 fold respectively. Using a combinatorial approach of multiple sequence alignment, surface topology, chemical modification and tryptic peptide mapping to identify the sequence of the heparin bound peptide; we demonstrate that heparin binds to the lysyl rich region of the F-helix of α-1-PI, which differs from that of heparin-antithrombin (AT) interactions. Molecular docking prediction using the MEDock algorithm approximates the three positively charged lysines (K154, K155, K174) of human α-1-PI in this interaction. This heparin α-1-PI interaction has been exploited to develop an affinity purification method, which can be used universally to obtain homogenous preparations of mammalian α-1-PIs useful for augmentation therapy. Collectively, all these findings imply that α-1-PI has a major role in regulating extra cellular protease activity and the physiological activator is heparin.

Item Type: Article
Uncontrolled Keywords: Association rate; Binding constant; Molecular docking; Antithrombin; pH stability
Subjects: 500 Natural Sciences and Mathematics > 04 Chemistry and Allied Sciences > 29 Protein Chemistry
Divisions: Protein Chemistry and Technology
Depositing User: Food Sci. & Technol. Information Services
Date Deposited: 09 Aug 2011 06:48
Last Modified: 09 Aug 2011 06:48
URI: http://ir.cftri.com/id/eprint/10435

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