ArticleJournal of thrombosis and haemostasis : JTH2018
The role of β-barrels 1 and 2 in the enzymatic activity of factor XIII A-subunit.
Article in Journal of thrombosis and haemostasis : JTH, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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3 citing papers in PubMed, 7 citations in OpenAlex.
- Association of fibrinogen and plasmin inhibitor, but not coagulation factor XIII gene polymorphisms with coronary artery disease.Journal of medical biochemistry · 2021Article
- Structure functional insights into calcium binding during the activation of coagulation factor XIII A.Scientific reports · 2019Article
- The role of β-barrels 1 and 2 in the enzymatic activity of factor XIII A-subunit.Journal of thrombosis and haemostasis : JTH · 2018Article
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10 authors at 2 institutions in 2 countries.
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Abstract
Essentials The roles of β-barrels 1 and 2 in factor XIII (FXIII) are currently unknown. FXIII truncations lacking β-barrel 2, both β-barrels, or full length FXIII, were made. Removing β-barrel 2 caused total loss of activity, removing both β-barrels returned 30% activity. β-barrel 2 is necessary for exposure of the active site cysteine during activation. SUMMARY: Background Factor XIII is composed of an activation peptide segment, a β-sandwich domain, a catalytic core, and, finally, β-barrels 1 and 2. FXIII is activated following cleavage of its A-subunits by thrombin. The resultant transglutaminase activity leads to increased resistance of fibrin clots to fibrinolysis. Objectives To assess the functional roles of β-barrels 1 and 2 in FXIII, we expressed and characterized the full-length FXIII A-subunit (FXIII-A) and variants truncated to residue 628 (truncated to β-barrel 1 [TB1]), residue 515 (truncated to catalytic core [TCC]), and residue 184 (truncated to β-sandwich). Methods Proteins were analyzed by gel electrophoresis, circular dichroism, fluorometric assays, and colorimetric activity assays, clot structure was analyzed by turbidity measurements and confocal microscopy, and clot formation was analyzed with a Chandler loop system. Results and Conclusions Circular dichroism spectroscopy and tryptophan fluorometry indicated that full-length FXIII-A and the truncation variants TCC and TB1 retain their secondary and tertiary structure. Removal of β-barrel 2 (TB1) resulted in total loss of transglutaminase activity, whereas the additional removal of β-barrel 1 (TCC) restored enzymatic activity to ~ 30% of that of full-length FXIII-A. These activity trends were observed with physiological substrates and smaller model substrates. Our data suggest that the β-barrel 1 domain protects the active site cysteine in the FXIII protransglutaminase, whereas the β-barrel 2 domain is necessary for exposure of the active site cysteine during activation. This study demonstrates the importance of individual β-barrel domains in modulating access to the FXIII active site region.
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