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

Journal Article · Fri Sep 01 04:00:00 EDT 1989 · Proceedings of the National Academy of Sciences of the United States of America; (USA)

DOI:https://doi.org/10.1073/pnas.86.17.6508· OSTI ID:7067339

Hill-Eubanks, D C; Parker, C G; Lollar, P ^[1]

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1. Univ. of Vermont, Burlington (USA)

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.

• OSTI ID: 7067339
• Journal Information: Proceedings of the National Academy of Sciences of the United States of America; (USA), Journal Name: Proceedings of the National Academy of Sciences of the United States of America; (USA) Vol. 86:17; ISSN 0027-8424; ISSN PNASA
• Country of Publication: United States
• Language: English

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59 BASIC BIOLOGICAL SCIENCES
ANIMALS
BETA DECAY RADIOISOTOPES
BIOCHEMISTRY
BIOLOGICAL MATERIALS
BLOOD
BLOOD COAGULATION FACTORS
BLOOD PLASMA
BODY FLUIDS
CHEMICAL ACTIVATION
CHEMICAL REACTIONS
CHEMISTRY
CHROMATOGRAPHY
COAGULANTS
DAYS LIVING RADIOISOTOPES
DECOMPOSITION
DISEASES
DRUGS
ELECTRON CAPTURE RADIOISOTOPES
ELECTROPHORESIS
ENZYMATIC HYDROLYSIS
ENZYMES
HEMATOLOGIC AGENTS
HEMIC DISEASES
HEMOPHILIA
HEMOSTATICS
HEREDITARY DISEASES
HYDROLASES
HYDROLYSIS
INTERMEDIATE MASS NUCLEI
IODINE 125
IODINE ISOTOPES
ION EXCHANGE CHROMATOGRAPHY
ISOTOPES
LYSIS
MAMMALS
MAN
MATERIALS
MOLECULAR STRUCTURE
NUCLEI
ODD-EVEN NUCLEI
ORGANIC COMPOUNDS
PEPTIDE HYDROLASES
PRIMATES
PROTEINS
RADIOISOTOPES
SEPARATION PROCESSES
SERINE PROTEINASES
SOLVOLYSIS
THROMBIN
VENOMS
VERTEBRATES