Cargando…
Cryo-EM structure of coagulation factor V short
Coagulation factor V (fV) is the precursor of activated fV (fVa), an essential component of the prothrombinase complex required for the rapid activation of prothrombin in the penultimate step of the coagulation cascade. In addition, fV regulates the tissue factor pathway inhibitor α (TFPIα) and prot...
Autores principales: | , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The American Society of Hematology
2023
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10356581/ https://www.ncbi.nlm.nih.gov/pubmed/36862974 http://dx.doi.org/10.1182/blood.2022019486 |
_version_ | 1785075308696698880 |
---|---|
author | Mohammed, Bassem M. Pelc, Leslie A. Rau, Michael J. Di Cera, Enrico |
author_facet | Mohammed, Bassem M. Pelc, Leslie A. Rau, Michael J. Di Cera, Enrico |
author_sort | Mohammed, Bassem M. |
collection | PubMed |
description | Coagulation factor V (fV) is the precursor of activated fV (fVa), an essential component of the prothrombinase complex required for the rapid activation of prothrombin in the penultimate step of the coagulation cascade. In addition, fV regulates the tissue factor pathway inhibitor α (TFPIα) and protein C pathways that inhibit the coagulation response. A recent cryogenic electron microscopy (cryo-EM) structure of fV has revealed the architecture of its A1-A2-B-A3-C1-C2 assembly but left the mechanism that keeps fV in its inactive state unresolved because of an intrinsic disorder in the B domain. A splice variant of fV, fV short, carries a large deletion of the B domain that produces constitutive fVa-like activity and unmasks epitopes for the binding of TFPIα. The cryo-EM structure of fV short was solved at 3.2 Å resolution and revealed the arrangement of the entire A1-A2-B-A3-C1-C2 assembly. The shorter B domain stretches across the entire width of the protein, making contacts with the A1, A2, and A3 domains but suspended over the C1 and C2 domains. In the portion distal to the splice site, several hydrophobic clusters and acidic residues provide a potential binding site for the basic C-terminal end of TFPIα. In fV, these epitopes may bind intramolecularly to the basic region of the B domain. The cryo-EM structure reported in this study advances our understanding of the mechanism that keeps fV in its inactive state, provides new targets for mutagenesis and facilitates future structural analysis of fV short in complex with TFPIα, protein S, and fXa. |
format | Online Article Text |
id | pubmed-10356581 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | The American Society of Hematology |
record_format | MEDLINE/PubMed |
spelling | pubmed-103565812023-07-21 Cryo-EM structure of coagulation factor V short Mohammed, Bassem M. Pelc, Leslie A. Rau, Michael J. Di Cera, Enrico Blood Thrombosis and Hemostasis Coagulation factor V (fV) is the precursor of activated fV (fVa), an essential component of the prothrombinase complex required for the rapid activation of prothrombin in the penultimate step of the coagulation cascade. In addition, fV regulates the tissue factor pathway inhibitor α (TFPIα) and protein C pathways that inhibit the coagulation response. A recent cryogenic electron microscopy (cryo-EM) structure of fV has revealed the architecture of its A1-A2-B-A3-C1-C2 assembly but left the mechanism that keeps fV in its inactive state unresolved because of an intrinsic disorder in the B domain. A splice variant of fV, fV short, carries a large deletion of the B domain that produces constitutive fVa-like activity and unmasks epitopes for the binding of TFPIα. The cryo-EM structure of fV short was solved at 3.2 Å resolution and revealed the arrangement of the entire A1-A2-B-A3-C1-C2 assembly. The shorter B domain stretches across the entire width of the protein, making contacts with the A1, A2, and A3 domains but suspended over the C1 and C2 domains. In the portion distal to the splice site, several hydrophobic clusters and acidic residues provide a potential binding site for the basic C-terminal end of TFPIα. In fV, these epitopes may bind intramolecularly to the basic region of the B domain. The cryo-EM structure reported in this study advances our understanding of the mechanism that keeps fV in its inactive state, provides new targets for mutagenesis and facilitates future structural analysis of fV short in complex with TFPIα, protein S, and fXa. The American Society of Hematology 2023-06-29 2023-03-07 /pmc/articles/PMC10356581/ /pubmed/36862974 http://dx.doi.org/10.1182/blood.2022019486 Text en © 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Thrombosis and Hemostasis Mohammed, Bassem M. Pelc, Leslie A. Rau, Michael J. Di Cera, Enrico Cryo-EM structure of coagulation factor V short |
title | Cryo-EM structure of coagulation factor V short |
title_full | Cryo-EM structure of coagulation factor V short |
title_fullStr | Cryo-EM structure of coagulation factor V short |
title_full_unstemmed | Cryo-EM structure of coagulation factor V short |
title_short | Cryo-EM structure of coagulation factor V short |
title_sort | cryo-em structure of coagulation factor v short |
topic | Thrombosis and Hemostasis |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10356581/ https://www.ncbi.nlm.nih.gov/pubmed/36862974 http://dx.doi.org/10.1182/blood.2022019486 |
work_keys_str_mv | AT mohammedbassemm cryoemstructureofcoagulationfactorvshort AT pelclesliea cryoemstructureofcoagulationfactorvshort AT raumichaelj cryoemstructureofcoagulationfactorvshort AT diceraenrico cryoemstructureofcoagulationfactorvshort |