ArticleBlood2012
Exposure of R169 controls protein C activation and autoactivation.
Article in Blood, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
18 citing papers in PubMed, 30 citations in OpenAlex.
- Thrombin has dual trypsin-like and chymotrypsin-like specificity.Journal of thrombosis and haemostasis : JTH · 2024Article
- From haemadin to haemanorm: Synthesis and characterization of full-length haemadin from the leech Haemadipsa sylvestris and of a novel bivalent, highly potent thrombin inhibitor (haemanorm).Protein science : a publication of the Protein Society · 2023Article
- Article
- The active site region plays a critical role in NaThe Journal of biological chemistry · 2022Article
- Zymogen and activated protein C have similar structural architecture.The Journal of biological chemistry · 2020Article
- Role of the activation peptide in the mechanism of protein C activation.Scientific reports · 2020Article
- Residues W215, E217 and E192 control the allosteric E*-E equilibrium of thrombin.Scientific reports · 2019Article
- Interplay between conformational selection and zymogen activation.Scientific reports · 2018Article
- Non-canonical proteolytic activation of human prothrombin by subtilisin fromThe Journal of biological chemistry · 2017Article
- Rational Design of Protein C Activators.Scientific reports · 2017Article
- Kinetic dissection of the pre-existing conformational equilibrium in the trypsin fold.The Journal of biological chemistry · 2015Article
- Why Ser and not Thr brokers catalysis in the trypsin fold.Biochemistry · 2015Article
- Article
- WEDGE: an anticoagulant thrombin mutant produced by autoactivation.Journal of thrombosis and haemostasis : JTH · 2015Article
- An allosteric switch for pro-HGF/Met signaling using zymogen activator peptides.Nature chemical biology · 2014Article
- Histone H4 promotes prothrombin autoactivation.The Journal of biological chemistry · 2013Article
- Autoactivation of thrombin precursors.The Journal of biological chemistry · 2013Article
- Down-regulation of the clotting cascade by the protein C pathway.Hematology education. European Hematology Association. Congress. Education Program · 2013Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Protein C is activated by thrombin with a value of k(cat)/K(m) = 0.11mM(-1)s(-1) that increases 1700-fold in the presence of the cofactor thrombomodulin. The molecular origin of this effect triggering an important feedback loop in the coagulation cascade remains elusive. Acidic residues in the activation domain of protein C are thought to electrostatically clash with the active site of thrombin. However, functional and structural data reported here support an alternative scenario. The thrombin precursor prethrombin-2 has R15 at the site of activation in ionic interaction with E14e, D14l, and E18, instead of being exposed to solvent for proteolytic attack. Residues E160, D167, and D172 around the site of activation at R169 of protein C occupy the same positions as E14e, D14l, and E18 in prethrombin-2. Caging of R169 by E160, D167, and D172 is responsible for much of the poor activity of thrombin toward protein C. The E160A/D167A/D172A mutant is activated by thrombin 63-fold faster than wild-type in the absence of thrombomodulin and, over a slower time scale, spontaneously converts to activated protein C. These findings establish a new paradigm for cofactor-assisted reactions in the coagulation cascade.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.