4.7 Article

Cryo-EM structures of human coagulation factors V and Va

期刊

BLOOD
卷 137, 期 22, 页码 3137-3144

出版社

AMER SOC HEMATOLOGY
DOI: 10.1182/blood.2021010684

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资金

  1. National Institutes of Health (NIH)
  2. National Heart, Lung, and Blood Institute [HL049413, HL139554, HL147821]
  3. Washington University Center for Cellular Imaging - Washington University School of Medicine
  4. Children's Discovery Institute of Washington University
  5. St Louis Children's Hospital [CDI-CORE-2015-505, CDI-CORE-2019-813]
  6. Foundation for Barnes-Jewish Hospital [3770]
  7. Washington University Diabetes Research Center (NIH, National Institute of Diabetes and Digestive and Kidney Diseases) [DK020579]
  8. Washington University School of Medicine (NIH, National Cancer Institute) [CA091842]
  9. Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital

向作者/读者索取更多资源

The cryo-EM structures of human coagulation factors V and Va reveal their assembly and function mechanisms, offering a molecular understanding of the clotting process.
Coagulation factor V (fV) is the precursor of fVa, which, together with fXa, Ca2+, and phospholipids, defines the prothrombinase complex and activates prothrombin in the penultimate step of the coagulation cascade. We solved the cryogenic electron microscopy (cryo-EM) structures of human fV and fVa at atomic (3.3 angstrom) and near-atomic (4.4 angstrom) resolution, respectively. The structure of fV reveals the entire A1-A2-B-A3-C1-C2 assembly, but with a surprisingly disordered B domain. The C1 and C2 domains provide a platform for interaction with phospholipid membranes and support the A1 and A3 domains, with the A2 domain sitting on top of them. The B domain is highly dynamic and visible only for short segments connecting to the A2 and A3 domains. The A2 domain reveals all sites of proteolytic processing by thrombin and activated protein C, a partially buried epitope for binding fXa, and fully exposed epitopes for binding activated protein C and prothrombin. Removal of the B domain and activation to fVa exposes the sites of cleavage by activated protein C at R306 and R506 and produces increased disorder in the A1-A2-A3-C1-C2 assembly, especially in the C-terminal acidic portion of the A2 domain that is responsible for prothrombin binding. Ordering of this region and full exposure of the fXa epitope emerge as necessary steps in the assembly of the prothrombin-prothrombinase complex. These structures offer molecular context for the function of fV and fVa and pioneer the analysis of coagulation factors by cryo-EM.

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