9MOT

Cryo-EM structure of factor Va bound to activated protein C

Summary for 9MOT

• Entry DOI: 10.2210/pdb9mot/pdb
• EMDB information: 48481
• Descriptor: Coagulation factor Va heavy chain, Coagulation factor Va light chain, Vitamin K-dependent protein C heavy chain, ... (4 entities in total)
• Functional Keywords: coagulation, activated factor v, activated protein c, blood clotting
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 185276.90

Authors

Mohammed, B.M.,Basore, K.,Di Cera, E. (deposition date: 2024-12-27, release date: 2025-05-21, Last modification date: 2025-07-02)

Primary citation

Mohammed, B.M.,Basore, K.,Di Cera, E.
Cryo-EM structure of coagulation factor Va bound to activated protein C.
Blood, 145:3166-3177, 2025

PubMed Abstract: Coagulation factor Va (fVa) is the cofactor component of the prothrombinase complex required for rapid generation of thrombin from prothrombin in the penultimate step of the coagulation cascade. In addition, fVa is a target for proteolytic inactivation by activated protein C (APC). Like other protein-protein interactions in the coagulation cascade, the fVa-APC interaction has long posed a challenge to structural biology and its molecular underpinnings remain unknown. A recent cryogenic electron microscopy (cryo-EM) structure of fVa has revealed the arrangement of its A1-A2-A3-C1-C2 domains and the environment of the sites of APC cleavage at R306 and R506. Here we report the cryo-EM structure of the fVa-APC complex at 3.15 Å resolution where the protease domain of APC engages R506 in the A2 domain of fVa mainly through electrostatic interactions between positively charged residues in the 30- and 70- loops of APC and an electronegative surface of fVa. The auxiliary Gla and EGF domains of APC are highly dynamic and point to solvent, without making contacts with fVa. Binding of APC displaces a large portion of the A2 domain of fVa and projects the 654VKCIPDDDEDSYEIFEP670 segment as a "latch", or exosite ligand, over the 70-loop of the enzyme. The latch induces a large conformational change of the autolysis loop of APC which in turn promotes docking of R506 into the primary specificity pocket. The cryo-EM structure of the fVa-APC complex validates the bulk of existing biochemical data and offers molecular context for a key regulatory interaction of the coagulation cascade.

PubMed: 40324068
DOI: 10.1182/blood.2025028476

Experimental method

ELECTRON MICROSCOPY (3.15 Å)