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Blood coagulation factors V and VIII: Molecular Mechanisms of Procofactor Activation.

ABSTRACT: A hallmark of hemostasis is that cells and proteins involved in the formation of a blood clot remain in a quiescent state and are only activated following an appropriate stimulus. The homologous proteins factors V and VIII cannot participate to any significant degree in their macromolecular enzyme complexes and are thus considered procofactors. Activity is generated following limited proteolysis, indicating that the conversion of the procofactors to factor Va and factor VIIIa must result in structural changes that impart cofactor function. The proteolytic events that lead to the activation of these proteins have been extensively characterized over the past three decades. However, a fundamental understanding of the mechanism(s) by which these proteins are kept as inactive procofactors and how specific bond cleavage facilitates the conversion to the active cofactor state is only starting to become known. These molecular processes undoubtedly play critical regulatory roles, evolved to maintain normal hemostasis since factor Va and factor VIIIa have a tremendous influence on thrombin generation. This review will detail our current understanding of the molecular process of procofactor activation and highlight structural features that play a major role in factor V and factor VIII activation.

SUBMITTER: Bos MH

PROVIDER: S-EPMC3001592 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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Blood coagulation factors V and VIII: Molecular Mechanisms of Procofactor Activation.

Bos Mettine H A MH Camire Rodney M RM

Journal of coagulation disorders 20100701 2

A hallmark of hemostasis is that cells and proteins involved in the formation of a blood clot remain in a quiescent state and are only activated following an appropriate stimulus. The homologous proteins factors V and VIII cannot participate to any significant degree in their macromolecular enzyme complexes and are thus considered procofactors. Activity is generated following limited proteolysis, indicating that the conversion of the procofactors to factor Va and factor VIIIa must result in stru ...[more]

PMID: 21165149

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Project description:BackgroundHuman blood coagulation factor VIII (fVIII) is a large plasma glycoprotein with sequential domain arrangement in the order A1-a1-A2-a2-B-a3-A3-C1-C2. The A1, A2 and A3 domains are interconnected by long linker peptides (a1, a2 and a3) that possess the activation sites. Proteolysis of fVIII zymogen by thrombin or factor Xa results in the generation of the activated form (fVIIIa) which serves as a critical co-factor for factor IXa (fIXa) enzyme in the intrinsic coagulation pathway.ResultsIn our efforts to elucidate the structural differences between fVIII and fVIIIa, we developed the solution structural models of both forms, starting from an incomplete 3.7 A X-ray crystal structure of fVIII zymogen, using explicit solvent MD simulations. The full assembly of B-domainless single-chain fVIII was built between the A1-A2 (Ala1-Arg740) and A3-C1-C2 (Ser1669-Tyr2332) domains. The structural dynamics of fVIII and fVIIIa, simulated for over 70 ns of time scale, enabled us to evaluate the integral motions of the multi-domain assembly of the co-factor and the possible coordination pattern of the functionally important calcium and copper ion binding in the protein.ConclusionsMD simulations predicted that the acidic linker peptide (a1) between the A1 and A2 domains is largely flexible and appears to mask the exposure of putative fIXa enzyme binding loop (Tyr555-Asp569) region in the A2 domain. The simulation of fVIIIa, generated from the zymogen structure, predicted that the linker peptide (a1) undergoes significant conformational reorganization upon activation by relocating completely to the A1-domain. The conformational transition led to the exposure of the Tyr555-Asp569 loop and the surrounding region in the A2 domain. While the proposed linker peptide conformation is predictive in nature and warrants further experimental validation, the observed conformational differences between the zymogen and activated forms may explain and support the large body of experimental data that implicated the critical importance of the cleavage of the peptide bond between the Arg372 and Ser373 residues for the full co-factor activity of fVIII.

Dataset Information

Blood coagulation factors V and VIII: Molecular Mechanisms of Procofactor Activation.

Publications

Blood coagulation factors V and VIII: Molecular Mechanisms of Procofactor Activation.

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