A frequent human coagulation Factor VII mutation (A294V, c152) in loop 140s affects the interaction with activators, tissue factor and substrates

The Biochemical Journal
Raffaella TosoFrancesco Bernardi

Abstract

Activated Factor VII (FVIIa) is a vitamin-K-dependent serine protease that initiates blood clotting after interacting with its cofactor tissue factor (TF). The complex FVIIa-TF is responsible for the activation of Factor IX (FIX) and Factor X (FX), leading ultimately to the formation of a stable fibrin clot. Activated FX (FXa), a product of FVIIa enzymic activity, is also the most efficient activator of zymogen FVII. Interactions of FVII/FVIIa with its activators, cofactor and substrates have been investigated extensively to define contact regions and residues involved in the formation of the complexes. Site-directed mutagenesis and inhibition assays led to the identification of sites removed from the FVIIa active site that influence binding specificity and affinity of the enzyme. In this study we report the characterization of a frequent naturally occurring human FVII mutant, A294V (residue 152 in the chymotrypsin numbering system), located in loop 140s. This region undergoes major rearrangements after FVII activation and is relevant to the development of substrate specificity. FVII A294V shows delayed activation by FXa as well as reduced activity towards peptidyl and macromolecular substrates without impairing the catalytic e...Continue Reading

References

Nov 28, 1989·Biochemistry·A H PedersenL C Petersen
May 20, 1988·Cell·B Furie, B C Furie
Feb 1, 1973·Proceedings of the National Academy of Sciences of the United States of America·Y Nemerson, M P Esnouf
Apr 20, 1967·Biochemical and Biophysical Research Communications·I Schechter, A Berger
Oct 15, 1993·European Journal of Biochemistry·A Kumar, D S Fair
Oct 25, 1996·The Journal of Biological Chemistry·S HigashiS Iwanaga
Dec 10, 1996·Proceedings of the National Academy of Sciences of the United States of America·C D DickinsonW Ruf
Dec 31, 1997·Arteriosclerosis, Thrombosis, and Vascular Biology·M HunaultK A Bauer
Aug 4, 1999·Proceedings of the National Academy of Sciences of the United States of America·A C PikeE Persson
Nov 2, 1999·Journal of Structural Biology·G Kemball-CookK Harlos
Apr 13, 2000·Nature·M S DennisR A Lazarus
Jun 22, 2000·Human Mutation·K Wulff, F H Herrmann
Jun 5, 2001·The Journal of Biological Chemistry·E PerssonO H Olsen
Jul 19, 2001·Proceedings of the National Academy of Sciences of the United States of America·J SheehanP Jagadeeswaran

❮ Previous
Next ❯

Citations

Mar 10, 2010·Biotechnology Letters·Nasser MasrooriMehryar Habibi Roudkenar
Sep 14, 2011·Journal of Biomedicine & Biotechnology·Sina MirzaahmadiBahram Kazemi
Oct 1, 2004·Journal of Thrombosis and Haemostasis : JTH·Y Fromovich-AmitU Seligsohn
Nov 25, 2003·Journal of Thrombosis and Haemostasis : JTH·C Furlan FreguiaF Bernardi
Oct 3, 2003·Journal of Thrombosis and Haemostasis : JTH·G MarianiUNKNOWN International Factor VII Deficiency Study Group
Feb 20, 2008·Haemophilia : the Official Journal of the World Federation of Hemophilia·S MartyM Giansily-Blaizot
Jun 18, 2015·Journal of Thrombosis and Haemostasis : JTH·A BranchiniM Pinotti
Apr 2, 2004·The Journal of Clinical Investigation·Paris MargaritisKatherine A High

❮ Previous
Next ❯

Related Concepts

Related Feeds

Blood Clotting Disorders

Thrombophilia includes conditions with increased tendency for excessive blood clotting. Blood clotting occurs when the body has insufficient amounts of specialized proteins that make blood clot and stop bleeding. Here is the latest research on blood clotting disorders.