ArticleThe Journal of biological chemistry2016
How the Linker Connecting the Two Kringles Influences Activation and Conformational Plasticity of Prothrombin.
Article in The Journal of biological chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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23 citing papers in PubMed, 37 citations in OpenAlex.
- Molecular mechanism of cleavage at R271 during prothrombin activation revealed by cryo-EM.Blood · 2026Article
- In vivo targeting of open prothrombin with the monoclonal antibody POmAb results in anticoagulation without excessive bleeding.Journal of thrombosis and haemostasis : JTH · 2026Article
- Serious issues with cryo-EM structures of human prothrombinase.Open biology · 2025Review
- Article
- The Prothrombin-Prothrombinase Interaction.Sub-cellular biochemistry · 2024Review
- Comparative sequence analysis of vitamin K-dependent coagulation factors.Journal of thrombosis and haemostasis : JTH · 2022Article
- Cryo-EM structures of coagulation factors.Research and practice in thrombosis and haemostasis · 2022Review
- Article
- Predicting protein-membrane interfaces of peripheral membrane proteins using ensemble machine learning.Briefings in bioinformatics · 2022Article
- Anti-prothrombin autoantibodies enriched after infection with SARS-CoV-2 and influenced by strength of antibody response against SARS-CoV-2 proteins.PLoS pathogens · 2021Article
- Exosite Binding in Thrombin: A Global Structural/Dynamic Overview of Complexes with Aptamers and Other Ligands.International journal of molecular sciences · 2021Review
- Zymogen and activated protein C have similar structural architecture.The Journal of biological chemistry · 2020Article
- Residues W215, E217 and E192 control the allosteric E*-E equilibrium of thrombin.Scientific reports · 2019Article
- Discovery and characterization of 2 novel subpopulations of aPS/PT antibodies in patients at high risk of thrombosis.Blood advances · 2019Article
- Probing prothrombin structure by limited proteolysis.Scientific reports · 2019Article
- Enhancing the anticoagulant profile of meizothrombin.Biomolecular concepts · 2018Article
- Interplay between conformational selection and zymogen activation.Scientific reports · 2018Article
- Structure of prothrombin in the closed form reveals new details on the mechanism of activation.Scientific reports · 2018Article
- Structure of Coagulation Factor II: Molecular Mechanism of Thrombin Generation and Development of Next-Generation Anticoagulants.Frontiers in medicine · 2018Review
- Non-canonical proteolytic activation of human prothrombin by subtilisin fromThe Journal of biological chemistry · 2017Article
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
A flexible linker (Lnk2) composed of 26 amino acids connects kringle-1 to kringle-2 in the coagulation factor prothrombin. Recent studies point to Lnk2 as a key determinant of the structure and function of this zymogen. Using a combination of mutagenesis, structural biology, and single molecule spectroscopy, we show how Lnk2 influences activation and conformational plasticity of prothrombin. Scrambling the sequence of Lnk2 is inconsequential on activation, and so is extension by as many as 22 residues. On the other hand, below a critical length of 15 residues, the rate of prothrombin activation increases (10-fold) in the absence of cofactor Va and decreases (3-fold) in the presence of cofactor. Furthermore, activation by prothrombinase takes place without preference along the prethrombin-2 (cleavage at Arg(271) first) or meizothrombin (cleavage at Arg(320) first) pathways. Notably, these transitions in the rate and pathway of activation require the presence of phospholipids, pointing to an important physiological role for Lnk2 when prothrombin is anchored to the membrane. Two new crystal structures of prothrombin lacking 22 (ProTΔ146-167) or 14 (ProTΔ154-167) residues of Lnk2 document striking conformational rearrangements of domains located across this linker. FRET measurements of freely diffusing single molecules prove that these structural transitions are genuine properties of the zymogen in solution. These findings support a molecular model of prothrombin activation where Lnk2 presents the sites of cleavage at Arg(271) and Arg(320) to factor Xa in different orientations by pivoting the C-terminal kringle-2/protease domain pair on the N-terminal Gla domain/kringle-1 pair anchored to the membrane.
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