AI Article Synopsis
- * The research utilized single-molecule Förster resonance energy transfer to investigate the structure of FXa, revealing that it behaves similarly in free form and when bound to physiologic substrates.
- * Results suggest major conformational changes in FXa occur when calcium is absent, indicating that vitamin K antagonists could affect its structure by disrupting the Gla domain’s interaction with calcium ions.
Article Abstract
Background: All current X-ray structures of factor (F)Xa are devoid of the γ-carboxyglutamate (Gla) domain and fail to reveal the overall conformation of the free protein. The recent cryogenic electron microscopy (cryo-EM) structure of FXa in the prothrombinase complex is the only structure of full-length FXa and shows that the Gla domain is positioned at an angle relative to the epidermal growth factor 1 domain.
Objectives: Establish if the curved conformation of FXa revealed by cryo-EM is also present in solution.
Methods: The conformation of FXa in solution was studied by single-molecule Förster resonance energy transfer.
Results: The conformation of full-length FXa in solution is resolved for the first time. The conformation is curved and extremely sensitive to Ca. It does not differ significantly from its zymogen form or from that present in the prothrombinase complex free or bound to the physiologic substrates prothrombin and meizothrombin.
Conclusion: Measurements by single-molecule Förster resonance energy transfer reveal that FXa has a curved conformation in solution, free or bound to physiologic ligands, and validate the recent cryo-EM structures of prothrombinase. The drastic conformational changes observed in the absence of Ca suggest that the structural architecture of FXa changes upon administration of vitamin K antagonists that perturb the interaction of the Gla domain with divalent cations.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11416302 | PMC |
| http://dx.doi.org/10.1016/j.jtha.2024.07.003 | DOI Listing |
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