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| Title | Cryo-EM structure of coagulation factor V short. |
|---|---|
| Journal, issue, pages | Blood, Vol. 141, Issue 26, Page 3215-3225, Year 2023 |
| Publish date | Jun 29, 2023 |
 Authors | Bassem M Mohammed / Leslie A Pelc / Michael J Rau / Enrico Di Cera /  |
| PubMed Abstract | 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 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. |
 External links | Blood / PubMed:36862974 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 3.2 Å |
| Structure data |  EMDB-29008: Cryo-EM structure of coagulation factor V short  EMDB-29009: Cryo-EM structure of coagulation factor V short  EMDB-29010: Cryo-EM structure of coagulation factor V short EMDB-29011, PDB-8fdg: |
| Source |
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 Keywords |  BLOOD CLOTTING |
