By Increasing the Affinity of Heparin for Fibrin, Zn2+ Promotes the Formation of a Ternary Heparin鈥揟hrombin鈥揊ibrin Complex That Protects Thrombin from Inhibition by Antithrombin

详细信息    查看全文

• 作者：Howard H. Chan ; Beverly A. Leslie ; Alan R. Stafford ; Robin S. Roberts ; Nadine N. Al-Aswad ; James C. Fredenburgh ; Jeffrey I. Weitz
• 刊名：Biochemistry
• 出版年：2012
• 出版时间：October 9, 2012
• 年：2012
• 卷：51
• 期：40
• 页码：7964-7973
• 全文大小：376K
• 年卷期：v.51,no.40(October 9, 2012)
• ISSN：1520-4995

文摘

Heparin binds fibrin and, by bridging thrombin onto fibrin, promotes the formation of a ternary heparin鈥搕hrombin鈥揻ibrin complex that protects thrombin from inhibition by antithrombin. Because thrombin binds 纬_A/纬鈥?fibrin, a variant with an extended 纬-chain, with higher affinity than the bulk 纬_A/纬_A-fibrin, 纬_A/纬鈥?fibrin affords bound thrombin more protection from inhibition by antithrombin鈥揾eparin. We examined the effect of Zn²⁺ on heparin鈥搕hrombin鈥揻ibrin complex formation because Zn²⁺ modulates heparin鈥損rotein interactions. Zn²⁺ increased the affinity of heparin for 纬_A/纬_A- and 纬_A/纬鈥?fibrin by 4.3- and 3.7-fold, respectively, but had no effect on the affinity of thrombin for either form of fibrin. In contrast, in the presence of heparin, Zn²⁺ increased the affinity of thrombin for 纬_A/纬_A-fibrin 4-fold (from a K_d value of 0.8 to 0.2 渭M) and slowed the rate of thrombin dissociation from 纬_A/纬_A-fibrin clots. These findings suggest that Zn²⁺ enhances the formation of ternary heparin鈥搕hrombin鈥揻ibrin complexes with 纬_A/纬_A-fibrin but does not influence the already high affinity interaction of thrombin with 纬_A/纬鈥?fibrin. Consistent with this concept, in the presence of Zn²⁺, 纬_A/纬_A-fibrin protected thrombin from inhibition by antithrombin鈥揾eparin to a similar extent as 纬_A/纬鈥?fibrin. Therefore, by enhancing the binding of heparin to fibrin, physiological concentrations of Zn²⁺ render fibrin-bound thrombin more protected from inhibition by antithrombin. Because fibrin-bound thrombin can trigger thrombus expansion, these findings help to explain why recurrent thrombosis can occur despite heparin treatment.