Amino acid residues of heparin cofactor II required for stimulation of thrombin inhibition by sulphated polyanions

Colwell, Niall S.; Grupe, Michael J; Tollefsen, Douglas M.

doi:10.1016/s0167-4838(99)00051-5

Cited by 21 publications

(19 citation statements)

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“…However, unlike AT, HCII requires no specific heparin sequence for this interaction (Huntington, 2006); other polyanions can also bind to HCII (Colwell et al, 1999). There is evidence, however, that binding to dermatan sulfate favors a hexasaccharide in which the IdoA residues are 2-Osulfated and the GalNAc is 4-sulfated (Maimone and Tollefsen, 1991); a 2-O-sulfated, 6-O-sulfated dermatanlike polysaccharide isolated from a sea squirt has almost no ability to potentiate HCII (Pavão et al, 1998).…”

Section: Other Heparin-activated Serpinsmentioning

confidence: 99%

Pharmacology of Heparin and Related Drugs

et al. 2015

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Section: Other Heparin-activated Serpinsmentioning

confidence: 99%

Pharmacology of Heparin and Related Drugs

et al. 2015

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“…15 Certain other natural, synthetic, or semi-synthetic polyanions, some of which are of pharmacological interest, also stimulate HCII activity. 16 In comparison with antithrombin, much higher concentrations of heparin or heparan sulfate are necessary to activate HCII, 15 and HCII is activated by heparin chains that lack the 3-O-sulfated glucosamine residues required for high-affinity binding to antithrombin (Figure 1). 17 When present in plasma at typical therapeutic concentrations, heparin preferentially stimulates antithrombin.…”

Section: Biochemistry Of Hciimentioning

confidence: 99%

Heparin Cofactor II Modulates the Response to Vascular Injury

Tollefsen

2007

ATVB

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Abstract-Heparin cofactor II (HCII) has several biochemical properties that distinguish it from other serpins: (1) it specifically inhibits thrombin; (2) the mechanism of inhibition involves binding of an acidic domain in HCII to thrombin exosite I; and (3) the rate of inhibition increases dramatically in the presence of dermatan sulfate molecules having specific structures. Human studies suggest that high plasma HCII levels are protective against in-stent restenosis and atherosclerosis. Studies with HCII knockout mice directly support the hypothesis that HCII interacts with dermatan sulfate in the arterial wall after endothelial injury and thereby exerts an antithrombotic effect. In addition, HCII deficiency appears to promote neointima formation and atherogenesis in mice. These results suggest that HCII plays a unique and important role in vascular homeostasis. Key Words: heparin cofactor II Ⅲ thrombin Ⅲ thrombosis Ⅲ atherogenesis Ⅲ restenosis T hirty years have elapsed since Briginshaw and Shanberge demonstrated that human plasma contains 2 heparindependent inhibitors of thrombin. 1,2 They reported that the 2 inhibitors could be separated by gel filtration and ionexchange chromatography. One of the inhibitors resembled the known protein antithrombin (formerly called antithrombin III) because it inactivated both thrombin and factor Xa and had easily detectable progressive (ie, heparinindependent) antithrombin activity. The second inhibitor did not react with factor Xa and had comparatively weak progressive antithrombin activity, yet it appeared to comprise a significant fraction of the total heparin cofactor activity in plasma. A few years later, Tollefsen and Blank demonstrated that 125 I-thrombin forms 2 SDS-stable complexes in plasma containing heparin, 3 and other investigators noted that the heparin cofactor activity of plasma exceeds the amount predicted from the antithrombin antigen concentration. 4,5 The existence of a second heparin cofactor (now called heparin cofactor II or HCII) was firmly established when the inhibitor was purified to homogeneity from human plasma and was shown to be distinct from antithrombin. 6 Although much has been learned about the structure, mechanism of action, and genetics of HCII, relatively little is known about its physiological function. This review summarizes our current knowledge of the biochemistry of HCII and then focus on recent insights gained from clinical studies and experiments with knockout mice. Biochemistry of HCIIThe HCII gene (designated SERPIND1 in humans) has been identified in a variety of vertebrate species, including humans, chimpanzee, rhesus monkey, house mouse, Norway rat, rabbit, cow, chicken, African clawed frog, European flounder, and zebrafish (http://www.ncbi.nlm.nih.gov/ entrez/). HCII mRNA is highly expressed in the liver, which appears to be the major source of plasma HCII. 7 Low levels of HCII mRNA are also detectable in other tissues, but the significance of extrahepatic expression of HCII is unclear. 8 HCII circulates in human plasma at...

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“…No acidic N-terminal sequence is present in AT, and the heparin-catalyzed thrombin inactivation mechanism is driven by template formation, as evidenced by the bell-shaped, logarithmic dependence of the inactivation rate constant on the heparin concentration (30). Bell-shaped inactivation profiles have also been reported for GAG-catalyzed thrombin inactivation (4,12,31,32), meizothrombin (MzT), and meizothrombin (des-fragment 1) (MzT(-F1)) inactivation by HCII (33). However, unlike for the heparin-catalyzed thrombin-AT reaction, no mechanism is available for the GAG-catalyzed thrombin-HCII reaction that simultaneously describes the template and allosteric behavior, and fits the GAG and HCII dependences of the inactivation rate constant, consistent with independently obtained protein-GAG binding constants.…”

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confidence: 99%

The Preferred Pathway of Glycosaminoglycan-accelerated Inactivation of Thrombin by Heparin Cofactor II

Verhamme

Bock

Jackson³

2004

Journal of Biological Chemistry

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Thrombin (T) inactivation by the serpin, heparin cofactor II (HCII), is accelerated by the glycosaminoglycans (GAGs) dermatan sulfate (DS) and heparin (H). Equilibrium binding and thrombin inactivationThe blood clotting proteinase, ␣-thrombin (T), 1 possesses two electropositive sites, exosites I and II (1, 2), that play distinct roles in its covalent inactivation by the serine proteinase inhibitors (serpins), antithrombin (AT), and heparin cofactor II (HCII), in the absence and presence of rate-accelerating glycosaminoglycans (GAGs) (3-8 (9,10). Inactivation by AT is accelerated up to 50,000-fold by high molecular weight heparin, which acts as a template, by binding to thrombin exosite II and AT helices A and D (4, 11). Whereas heparin accelerates thrombin inactivation by both AT and HCII, dermatan sulfate (DS), and other polyanions (5, 12-17) selectively enhance HCII inhibitory action. The HCII mechanism was initially thought to utilize GAGs as templates between exosite II and HCII helix D (5, 12, 13), but later hypothesized to involve allosteric, GAG-induced interaction of an acidic N-terminal domain of HCII with exosite I (6, 7, 18 -21). A synthetic HCII-(54 -75) peptide was shown to compete with hirudin-(54 -65) for thrombin binding (18). Residues 52-75 in HCII contain two hirudin-like repeats, the first of which interacts directly with exosite I (21). The crystal structure of the HCII⅐S195A-thrombin Michaelis complex confirmed this exosite I interaction (22). Deletion of the first HCII acidic repeat (6,19), and mutations in exosite I residues Arg 67 and Arg 73 (20) caused large decreases in the rate constants for the heparin-and DS-catalyzed inactivation, further suggesting the importance of the direct HCII-exosite I interaction. Selective thrombin exosite II mutations did not affect the DS-catalyzed inactivation rate significantly (23,24). Blocking exosite II with HD22, a single-stranded DNA aptamer only had a modest effect on this inactivation rate, and DS with a chain length of 12-20 saccharide units was found to be as effective as higher M r DS in catalyzing thrombin inactivation (25). Whereas some studies report DS binding to thrombin (13,23,26), others postulate that DS does not interact with thrombin (27, 28). These findings, and the assumption that DS template action, like heparin, engages exosite II, led to the proposal of a mechanism in which direct interaction of the HCII N-terminal domain with exosite I is predominant, and GAG template action may be less important, or not even obligatory.In the mechanism of high affinity heparin-catalyzed throm-

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Amino acid residues of heparin cofactor II required for stimulation of thrombin inhibition by sulphated polyanions

Cited by 21 publications

References 35 publications

Pharmacology of Heparin and Related Drugs

Pharmacology of Heparin and Related Drugs

Heparin Cofactor II Modulates the Response to Vascular Injury

The Preferred Pathway of Glycosaminoglycan-accelerated Inactivation of Thrombin by Heparin Cofactor II

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