FEBS Lett. 2009 Nov 3;583(21):3397-400. Epub 2009 Oct 9.

Activation of antithrombin as a factor IXa and Xa inhibitor involves mitigation of repression rather than positive enhancement.

Source

Department of Biochemistry and Molecular Genetics, and Center for Structural Biology, University of Illinois at Chicago, IL 60612-4316, USA. pgettins@uic.edu

Abstract

Allosteric activation of antithrombin as a rapid inhibitor of factors IXa and Xa requires binding of a high-affinity heparin pentasaccharide. The currently-accepted mechanism involves removal of a constraint on the antithrombin reactive center loop (RCL) so that the proteinase can simultaneously engage both the P1 arginine and an exosite at Y253. Recent results suggest that this mechanism is incorrect in that activation can be achieved without loop expulsion, while the exosite can be engaged in both low and high activity states. We propose a quite different mechanism in which heparin activates antithrombin by mitigating an unfavorable surface interaction, by altering its nature, and by moving the attached proteinase away from the site of the unfavorable interaction through RCL expulsion.

PMID:: 19818773; [PubMed - indexed for MEDLINE]

Publication Types, MeSH Terms, Substances, Grant Support

Publication Types

Research Support, N.I.H., Extramural

MeSH Terms

Substances

Grant Support

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Blood Thinners - MedlinePlus Health Information

Molecular Biology Databases

HEPARIN - HSDB

Supplemental Content

Save items

Related citations in PubMed

Localization of an antithrombin exosite that promotes rapid inhibition of factors Xa and IXa dependent on heparin activation of the serpin. [J Biol Chem. 2003]
Localization of an antithrombin exosite that promotes rapid inhibition of factors Xa and IXa dependent on heparin activation of the serpin.
Izaguirre G, Zhang W, Swanson R, Bedsted T, Olson ST. J Biol Chem. 2003 Dec 19; 278(51):51433-40. Epub 2003 Oct 7.
Residues Tyr253 and Glu255 in strand 3 of beta-sheet C of antithrombin are key determinants of an exosite made accessible by heparin activation to promote rapid inhibition of factors Xa and IXa. [J Biol Chem. 2006]
Residues Tyr253 and Glu255 in strand 3 of beta-sheet C of antithrombin are key determinants of an exosite made accessible by heparin activation to promote rapid inhibition of factors Xa and IXa.
Izaguirre G, Olson ST. J Biol Chem. 2006 May 12; 281(19):13424-32. Epub 2006 Mar 3.
Conformational equilibrium of the reactive center loop of antithrombin examined by steady state and time-resolved fluorescence measurements: consequences for the mechanism of factor Xa inhibition by antithrombin-heparin complexes. [Biochemistry. 2001]
Conformational equilibrium of the reactive center loop of antithrombin examined by steady state and time-resolved fluorescence measurements: consequences for the mechanism of factor Xa inhibition by antithrombin-heparin complexes.
Futamura A, Beechem JM, Gettins PG. Biochemistry. 2001 Jun 5; 40(22):6680-7.
Review Role of heparin and heparinlike molecules in thrombosis and atherosclerosis. [Fed Proc. 1985]
Review Role of heparin and heparinlike molecules in thrombosis and atherosclerosis.
Rosenberg RD. Fed Proc. 1985 Feb; 44(2):404-9.
Review Mechanism of heparin action. [Baillieres Clin Haematol. 1990]
Review Mechanism of heparin action.
Jackson CM. Baillieres Clin Haematol. 1990 Jul; 3(3):483-504.

See reviews... See all...

Cited by 4 PubMed Central articles

Kinetic evidence that allosteric activation of antithrombin by heparin is mediated by two sequential conformational changes. [Arch Biochem Biophys. 2010]
Kinetic evidence that allosteric activation of antithrombin by heparin is mediated by two sequential conformational changes.
Schedin-Weiss S, Richard B, Olson ST. Arch Biochem Biophys. 2010 Dec 15; 504(2):169-76. Epub 2010 Sep 15.
Review Molecular mechanisms of antithrombin-heparin regulation of blood clotting proteinases. A paradigm for understanding proteinase regulation by serpin family protein proteinase inhibitors. [Biochimie. 2010]
Review Molecular mechanisms of antithrombin-heparin regulation of blood clotting proteinases. A paradigm for understanding proteinase regulation by serpin family protein proteinase inhibitors.
Olson ST, Richard B, Izaguirre G, Schedin-Weiss S, Gettins PG. Biochimie. 2010 Nov; 92(11):1587-96. Epub 2010 Jun 2.
Role of the residues of the 39-loop in determining the substrate and inhibitor specificity of factor IXa. [J Biol Chem. 2010]
Role of the residues of the 39-loop in determining the substrate and inhibitor specificity of factor IXa.
Yang L, Manithody C, Qureshi SH, Rezaie AR. J Biol Chem. 2010 Sep 10; 285(37):28488-95. Epub 2010 Jul 13.

See all...

Related information

Related Citations
Calculated set of PubMed citations closely related to the selected article(s) retrieved using a word weight algorithm. Related articles are displayed in ranked order from most to least relevant, with the “linked from” citation displayed first.
Substance (MeSH Keyword)
PubChem chemical substance (submitted) records that are classified under the same Medical Subject Headings (MeSH) controlled vocabulary as the current articles.
Cited in PMC
Full-text articles in the PubMed Central Database that cite the current articles.

Recent activity

Clear Turn Off Turn On

Activation of antithrombin as a factor IXa and Xa inhibitor involves mitigation ...
Activation of antithrombin as a factor IXa and Xa inhibitor involves mitigation of repression rather than positive enhancement.
FEBS Lett. 2009 Nov 3 ;583(21):3397-400. Epub 2009 Oct 9 .

PubMed
The otubain YOD1 is a deubiquitinating enzyme that associates with p97 to facili...
The otubain YOD1 is a deubiquitinating enzyme that associates with p97 to facilitate protein dislocation from the ER.
Mol Cell. 2009 Oct 9 ;36(1):28-38.

PubMed
Effect of immunodeficiency, HIV viral load, and antiretroviral therapy on the ri...
Effect of immunodeficiency, HIV viral load, and antiretroviral therapy on the risk of individual malignancies (FHDH-ANRS CO4): a prospective cohort study.
Lancet Oncol. 2009 Dec ;10(12):1152-9. Epub 2009 Oct 7 .

PubMed
[Pharmacology of a new antihypertensive agent, metazosin (Kenosin)].
[Pharmacology of a new antihypertensive agent, metazosin (Kenosin)].
Cesk Farm. 1990 Jul ;39(6):266-74.

PubMed
MiRNA-29a regulates the expression of numerous proteins and reduces the invasive...
MiRNA-29a regulates the expression of numerous proteins and reduces the invasiveness and proliferation of human carcinoma cell lines.
Eur J Cancer. 2009 Nov ;45(17):3104-18. Epub 2009 Oct 7 .

PubMed

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

PubMed

Result Filters

Display Settings:

Send to: