Expression of allosteric linkage between the sodium ion binding site and exosite I of thrombin during prothrombin activation.

Expression of allosteric linkage between the sodium ion binding site and exosite I of thrombin during prothrombin activation. Research Abstract Details 

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Expression of allosteric linkage between the sodium ion binding site and exosite I of thrombin during prothrombin activation. Abstract Text:

Heather K Kroh,Guido Tans,Gerry A F Nicolaes,Jan Rosing,Paul E Bock,Heather K Kroh,Guido Tans,Gerry A F Nicolaes,Jan Rosing,Paul E Bock,

The specificity of thrombin for procoagulant and anticoagulant substrates is regulated allosterically by Na+. Ordered cleavage of prothrombin (ProT) at Arg320 by the prothrombinase complex generates proteolytically active, meizothrombin (MzT), followed by cleavage at Arg271 to produce thrombin and fragment 1.2. The alternative pathway of initial cleavage at Arg271 produces the inactive zymogen form, the prethrombin 2 (Pre 2).fragment 1.2 complex, which is cleaved subsequently at Arg320. Cleavage at Arg320 of ProT or prethrombin 1 (Pre 1) activates the catalytic site and the precursor form of exosite I (proexosite I). To determine the pathway of expression of Na+-(pro)exosite I linkage during ProT activation, the effects of Na+ on the affinity of fluorescein-labeled hirudin-(54-65) ([5F]Hir-(54-65)(SO-3)) for the zymogens, ProT, Pre 1, and Pre 2, and for the proteinases, MzT and MzT-desfragment 1 (MzT(-F1)) were quantitated. The zymogens showed no significant linkage between proexosite I and Na+, whereas cleavage at Arg320 caused the affinities of MzT and MzT(-F1) for [5F]Hir-(54-65)(SO-3) to be enhanced by Na+ 8- to 10-fold and 5- to 6-fold, respectively. MzT and MzT(-F1) showed kinetically different mechanisms of Na+ enhancement of chromogenic substrate hydrolysis. The results demonstrate for the first time that MzT is regulated allosterically by Na+. The results suggest that the distinctive procoagulant substrate specificity of MzT, in activating factor V and factor VIII on membranes, and the anticoagulant, membrane-modulated activation of protein C by MzT bound to thrombomodulin are regulated by Na+-induced allosteric transition. Further, the Na+ enhancement in MzT activity and exosite I affinity may function in directing the sequential ProT activation pathway by accelerating thrombin formation from the MzT fast form.

Expression of allosteric linkage between the sodium ion binding site and exosite I of thrombin during prothrombin activation. Publishing Authors By Initials

HK Kroh,G Tans,GA Nicolaes,J Rosing,PE Bock,HK Kroh,G Tans,GA Nicolaes,J Rosing,PE Bock,

For similar enzymes and coenzymes: enzymes: hydrolases: peptide hydrolases: endopeptidases: serine endopeptidases: thrombin research abstracts see: enzymes and coenzymes: enzymes: hydrolases: peptide hydrolases: endopeptidases: serine endopeptidases: thrombin research

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Expression of allosteric linkage between the sodium ion binding site and exosite I of thrombin during prothrombin activation. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: The Journal of biological chemistry

VOLUME: 282

Page Numbers: 16095-104

Journal Abbreviation: J. Biol. Chem.

ISSN: 0021-9258

DAY: 12

MONTH: 04

YEAR: 2007

Expression of allosteric linkage between the sodium ion binding site and exosite I of thrombin during prothrombin activation. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 2985121

Expression of allosteric linkage between the sodium ion binding site and exosite I of thrombin during prothrombin activation. Keywords Mesh Terms:

KEYWORDS: Thrombin

MESH TERMS: metabolism

Chemical & Substance for Abstract: Expression of allosteric linkage between the sodium ion binding site and exosite I of thrombin during prothrombin activation. Information

Substance Name: ecarin

Registry Number: EC 3.4.99.27

Grant and Affiliation Information for Expression of allosteric linkage between the sodium ion binding site and exosite I of thrombin during prothrombin activation.

AFFILIATION: Department of Pathology, Vanderbilt University, Nashville, Tennessee 37232, USA.

Country: United States

AGENCY: United States NHLBI

GRANT: HL038779

ACRONYM: HL

MEDLINETA: J Biol Chem

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