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Title: Differential proteolytic activation of factor VIII-von Willebrand factor complex by thrombin

Abstract

Blood coagulation factor VIII (fVIII) is a plasma protein that is decreased or absent in hemophilia A. It is isolated as a mixture of heterodimers that contain a variably sized heavy chain and a common light chain. Thrombin catalyzes the activation of fVIII in a reaction that is associated with cleavages in both types of chain. The authors isolated a serine protease from Bothrops jararacussu snake venom that catalyzes thrombin-like heavy-chain cleavage but not light-chain cleavage in porcine fVIII as judged by NaDodSO{sub 4}/PAGE and N-terminal sequence analysis. Using a plasma-free assay of the ability of activated {sup 125}I-fVIII to function as a cofactor in the activation of factor X by factor IXa, they found that fVIII is activated by the venom enzyme. The venom enzyme-activated fVIII was isolated in stable form by cation-exchange HPLC. von Willebrand factor inhibited venom enzyme-activated fVIII but not thrombin-activated fVIII. These results suggest that the binding of fVIII to von Willebrand factor depends on the presence of an intact light chain and that activated fVIII must dissociate from von Willebrand factor to exert its cofactor effect. Thus, proteolytic activation of fVIII-von Willebrand factor complex appears to be differentially regulated by light-chain cleavage to dissociatemore » the complex and heavy-chain cleavage to activate the cofactor function.« less

Authors:
; ;  [1]
  1. (Univ. of Vermont, Burlington (USA))
Publication Date:
OSTI Identifier:
7067339
Resource Type:
Journal Article
Resource Relation:
Journal Name: Proceedings of the National Academy of Sciences of the United States of America; (USA); Journal Volume: 86:17
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; BLOOD COAGULATION FACTORS; CHEMICAL ACTIVATION; THROMBIN; BIOCHEMISTRY; BLOOD PLASMA; ELECTROPHORESIS; ENZYMATIC HYDROLYSIS; HEMOPHILIA; IODINE 125; ION EXCHANGE CHROMATOGRAPHY; MAN; MOLECULAR STRUCTURE; SERINE PROTEINASES; VENOMS; ANIMALS; BETA DECAY RADIOISOTOPES; BIOLOGICAL MATERIALS; BLOOD; BODY FLUIDS; CHEMICAL REACTIONS; CHEMISTRY; CHROMATOGRAPHY; COAGULANTS; DAYS LIVING RADIOISOTOPES; DECOMPOSITION; DISEASES; DRUGS; ELECTRON CAPTURE RADIOISOTOPES; ENZYMES; HEMATOLOGIC AGENTS; HEMIC DISEASES; HEMOSTATICS; HEREDITARY DISEASES; HYDROLASES; HYDROLYSIS; INTERMEDIATE MASS NUCLEI; IODINE ISOTOPES; ISOTOPES; LYSIS; MAMMALS; MATERIALS; NUCLEI; ODD-EVEN NUCLEI; ORGANIC COMPOUNDS; PEPTIDE HYDROLASES; PRIMATES; PROTEINS; RADIOISOTOPES; SEPARATION PROCESSES; SOLVOLYSIS; VERTEBRATES; 550201* - Biochemistry- Tracer Techniques

Citation Formats

Hill-Eubanks, D.C., Parker, C.G., and Lollar, P. Differential proteolytic activation of factor VIII-von Willebrand factor complex by thrombin. United States: N. p., 1989. Web. doi:10.1073/pnas.86.17.6508.
Hill-Eubanks, D.C., Parker, C.G., & Lollar, P. Differential proteolytic activation of factor VIII-von Willebrand factor complex by thrombin. United States. doi:10.1073/pnas.86.17.6508.
Hill-Eubanks, D.C., Parker, C.G., and Lollar, P. Fri . "Differential proteolytic activation of factor VIII-von Willebrand factor complex by thrombin". United States. doi:10.1073/pnas.86.17.6508.
@article{osti_7067339,
title = {Differential proteolytic activation of factor VIII-von Willebrand factor complex by thrombin},
author = {Hill-Eubanks, D.C. and Parker, C.G. and Lollar, P.},
abstractNote = {Blood coagulation factor VIII (fVIII) is a plasma protein that is decreased or absent in hemophilia A. It is isolated as a mixture of heterodimers that contain a variably sized heavy chain and a common light chain. Thrombin catalyzes the activation of fVIII in a reaction that is associated with cleavages in both types of chain. The authors isolated a serine protease from Bothrops jararacussu snake venom that catalyzes thrombin-like heavy-chain cleavage but not light-chain cleavage in porcine fVIII as judged by NaDodSO{sub 4}/PAGE and N-terminal sequence analysis. Using a plasma-free assay of the ability of activated {sup 125}I-fVIII to function as a cofactor in the activation of factor X by factor IXa, they found that fVIII is activated by the venom enzyme. The venom enzyme-activated fVIII was isolated in stable form by cation-exchange HPLC. von Willebrand factor inhibited venom enzyme-activated fVIII but not thrombin-activated fVIII. These results suggest that the binding of fVIII to von Willebrand factor depends on the presence of an intact light chain and that activated fVIII must dissociate from von Willebrand factor to exert its cofactor effect. Thus, proteolytic activation of fVIII-von Willebrand factor complex appears to be differentially regulated by light-chain cleavage to dissociate the complex and heavy-chain cleavage to activate the cofactor function.},
doi = {10.1073/pnas.86.17.6508},
journal = {Proceedings of the National Academy of Sciences of the United States of America; (USA)},
number = ,
volume = 86:17,
place = {United States},
year = {Fri Sep 01 00:00:00 EDT 1989},
month = {Fri Sep 01 00:00:00 EDT 1989}
}