8FDG

Cryo-EM structure of coagulation factor V short

Summary for 8FDG

• Entry DOI: 10.2210/pdb8fdg/pdb
• EMDB information: 29008 29009 29010 29011
• Descriptor: Coagulation factor V (1 entity in total)
• Functional Keywords: blood clotting
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 1
• Total formula weight: 172748.23

Authors

Mohammed, B.M.,Pelc, L.A.,Rau, M.J.,Di Cera, E. (deposition date: 2022-12-03, release date: 2023-03-15, Last modification date: 2024-10-16)

Primary citation

Mohammed, B.M.,Pelc, L.A.,Rau, M.J.,Di Cera, E.
Cryo-EM structure of coagulation factor V short.
Blood, 141:3215-3225, 2023

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 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.

PubMed: 36862974
DOI: 10.1182/blood.2022019486

Experimental method

ELECTRON MICROSCOPY (3.2 Å)