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

作者：Gupta Vivek Kumar; Gowda Lalitha R^*

来源：Biochimie, 2008, 90(5): 749-761.

DOI：10.1016/j.biochi.2008.01.004

• association rate
• binding constant
• molecular docking
• antithrombin
• pH stability

Alpha-1-proteinase (alpha-1-PI) inhibitor is the major circulating serine protease inhibitor in humans. The porcine elastase and trypsin inhibitory activity of human and ovine alpha-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 K-ass for ovine and human alpha-1-PI inhibition of porcine pancreatic elastase was increased similar to 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 alpha-1-PI, which differs from that of heparin-antithrombin (AT) interactions. Molecular docking prediction using the MEDock algorithm approximates the three positively charged lysines (K-154, K-155, K-174) of human alpha-1-PI in this interaction. This heparin alpha-1-PI interaction has been exploited to develop an affinity purification method, which can be used universally to obtain homogenous preparations of mammalian alpha-1-PIs useful for augmentation therapy. Collectively, all these findings imply that alpha-1-PI has a major role in regulating extra cellular protease activity and the physiological activator is heparin.

• 出版日期2008-5