Heparin Binds Lamprey Angiotensinogen and Promotes Thrombin Inhibition through a Template Mechanism

Wei H, Cai H, Wu J, Wei Z, Zhang F, Huang X, Ma L, Feng L, Zhang R, Wang Y, Ragg H, et al. (2016)
JOURNAL OF BIOLOGICAL CHEMISTRY 291(48): 24900-+.

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Lamprey angiotensinogen (l-ANT) is a hormone carrier in the regulation of blood pressure, but it is also a heparin-dependent thrombin inhibitor in lamprey blood coagulation system. The detailed mechanisms on how angiotensin is carried by l-ANT and how heparin binds l-ANT and mediates thrombin inhibition are unclear. Here we have solved the crystal structure of cleaved l-ANT at 2.7 angstrom resolution and characterized its properties in heparin binding and protease inhibition. The structure reveals that l-ANT has a conserved serpin fold with a labile N-terminal angiotensin peptide and undergoes a typical stressed-to-relaxed conformational change when the reactive center loop is cleaved. Heparin binds l-ANT tightly with a dissociation constant of similar to 10 nM involving similar to 8 monosaccharides and similar to 6 ionic interactions. The heparin binding site is located in an extensive positively charged surface area around helix D involving residues Lys-148, Lys-151, Arg-155, and Arg-380. Although l-ANT by itself is a poor thrombin inhibitor with a second order rate constant of 500 M-1 s(-1), its interaction with thrombin is accelerated 90-fold by high molecular weight heparin following a bell-shaped dose-dependent curve. Short heparin chains of 6-20 monosaccharide units are insufficient to promote thrombin inhibition. Furthermore, an l-ANT mutant with the P1 Ile mutated to Arg inhibits thrombin nearly 1500-fold faster than the wild type, which is further accelerated by high molecular weight heparin. Taken together, these results suggest that heparin binds l-ANT at a conserved heparin binding site around helix D and promotes the interaction between l-ANT and thrombin through a template mechanism conserved in vertebrates.
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Wei H, Cai H, Wu J, et al. Heparin Binds Lamprey Angiotensinogen and Promotes Thrombin Inhibition through a Template Mechanism. JOURNAL OF BIOLOGICAL CHEMISTRY. 2016;291(48):24900-+.
Wei, H., Cai, H., Wu, J., Wei, Z., Zhang, F., Huang, X., Ma, L., et al. (2016). Heparin Binds Lamprey Angiotensinogen and Promotes Thrombin Inhibition through a Template Mechanism. JOURNAL OF BIOLOGICAL CHEMISTRY, 291(48), 24900-+. doi:10.1074/jbc.M116.725895
Wei, H., Cai, H., Wu, J., Wei, Z., Zhang, F., Huang, X., Ma, L., Feng, L., Zhang, R., Wang, Y., et al. (2016). Heparin Binds Lamprey Angiotensinogen and Promotes Thrombin Inhibition through a Template Mechanism. JOURNAL OF BIOLOGICAL CHEMISTRY 291, 24900-+.
Wei, H., et al., 2016. Heparin Binds Lamprey Angiotensinogen and Promotes Thrombin Inhibition through a Template Mechanism. JOURNAL OF BIOLOGICAL CHEMISTRY, 291(48), p 24900-+.
H. Wei, et al., “Heparin Binds Lamprey Angiotensinogen and Promotes Thrombin Inhibition through a Template Mechanism”, JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 291, 2016, pp. 24900-+.
Wei, H., Cai, H., Wu, J., Wei, Z., Zhang, F., Huang, X., Ma, L., Feng, L., Zhang, R., Wang, Y., Ragg, H., Zheng, Y., Zhou, A.: Heparin Binds Lamprey Angiotensinogen and Promotes Thrombin Inhibition through a Template Mechanism. JOURNAL OF BIOLOGICAL CHEMISTRY. 291, 24900-+ (2016).
Wei, Hudie, Cai, Haiyan, Wu, Jiawei, Wei, Zhenquan, Zhang, Fei, Huang, Xin, Ma, Lina, Feng, Lingling, Zhang, Ruoxi, Wang, Yunjie, Ragg, Hermann, Zheng, Ying, and Zhou, Aiwu. “Heparin Binds Lamprey Angiotensinogen and Promotes Thrombin Inhibition through a Template Mechanism”. JOURNAL OF BIOLOGICAL CHEMISTRY 291.48 (2016): 24900-+.
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