Arginine 200 of heparin cofactor II promotes intramolecular interactions of the acidic domain. Implication for thrombin inhibition.

The Journal of Biological Chemistry
A V CiacciaF C Church

Abstract

Heparin cofactor II (HCII) is presumed to be a physiological inhibitor of the serine proteinase thrombin. The reaction between HCII and thrombin is quite unique, because it involves an unusual HCII-reactive site loop sequence of Leu444-Ser445, requires the presence of glycosaminoglycans for optimal activity and involves a protein-protein interaction besides the reactive site loop-active site interaction characteristic of serine proteinase inhibitor-serine proteinase pairs. Two mutations at a unique HCII residue, Arg200 --> Ala or Glu, were generated by site-directed mutagenesis. The mutations did not alter either HCII binding to heparin-Sepharose or HCII inhibition of thrombin in the presence of heparin or dermatan sulfate, suggesting that Arg200 is not part of the glycosaminoglycan binding site of HCII. In the absence of glycosaminoglycan, there was a significant increase in alpha-thrombin inhibition by the Arg200 mutants as compared with wild type recombinant HCII (wt-rHCII), whereas inhibition rates with chymotrypsin were identical. Inhibition of gammaT-thrombin, which lacks anion-binding exosite 1 ((ABE-1), the region of alpha-thrombin that interacts with the acidic domain of HCII), was significantly reduced compared with a...Continue Reading

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Citations

Nov 6, 2007·Blood Coagulation & Fibrinolysis : an International Journal in Haemostasis and Thrombosis·Taro TaketomiKenichi A Tanaka
Jun 22, 2014·Immunobiology·Abhishek KumarChandan Goswami
Nov 27, 1999·The Journal of Biological Chemistry·S J Bauman, F C Church
Feb 7, 2001·The Journal of Biological Chemistry·Y HayakawaN Sakuragawa
Mar 28, 2009·International Journal of Molecular Sciences·Laura BonifacioMichael B Jarstfer
Mar 22, 2020·Nature Chemical Biology·James S ItaliaAbhishek Chatterjee

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