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Swapping the charges on the D and H‐Helix of Protein C Inhibitor alters heparin binding.
Author(s) -
Porath Jaclyn Anne,
Cooper Scott Thomas
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a48-a
Subject(s) - serpin , heparin , heparin cofactor ii , chemistry , antithrombin , serine protease , thrombin , protease inhibitor (pharmacology) , biochemistry , stimulation , binding site , antithrombins , protease , biophysics , biology , enzyme , platelet , endocrinology , immunology , human immunodeficiency virus (hiv) , antiretroviral therapy , viral load , gene
Protein C Inhibitor (PCI) is a member of the super‐family of serine protease inhibitors (serpins). PCI functions as a regulatory serpin in pathways involved in hemostatic control, tumor cell invasion, and fertility. The inhibitory activity of PCI is accelerated 40‐fold by the glycosaminoglycan heparin. This acceleration occurs when heparin binds to basic residues of the H‐helix and regions of the protease to form a bridge. Two other serpins, antithrombin and heparin cofactor II, also bind to heparin and this stimulates thrombin inhibition. However, the heparin binding sites in these serpins are on the D‐helix. We swapped the heparin binding sites in PCI, and demonstrate that loss of positive charges on the H‐helix removes heparin binding and heparin stimulation. Adding positive charges to the D‐helix increased heparin binding and heparin stimulation.