Abstract
The activation and regulation of coagulation Factor XIII (FXIII) protein has been the subject of active research for the past three decades. Although discrete evidence exists on various aspects of FXIII activation and regulation a combinatorial structure/functional view in this regard is lacking. In this study, we present results of a structure/function study of the functional chain of events for FXIII. Our study shows how subtle chronological submolecular changes within calcium binding sites can bring about the detailed transformation of the zymogenic FXIII to its activated form especially in the context of FXIIIA and FXIIIB subunit interactions. We demonstrate what aspects of FXIII are important for the stabilization (first calcium binding site) of its zymogenic form and the possible modes of deactivation (thrombin mediated secondary cleavage) of the activated form. Our study for the first time provides a structural outlook of the FXIIIA2B2 heterotetramer assembly, its association and dissociation. The FXIIIB subunits regulatory role in the overall process has also been elaborated upon. In summary, this study provides detailed structural insight into the mechanisms of FXIII activation and regulation that can be used as a template for the development of future highly specific therapeutic inhibitors targeting FXIII in pathological conditions like thrombosis.
Highlights
The fibrin stabilizing factor or coagulation factor XIII (FXIII) is a heterotetrameric protein complex, circulating in the plasma as a 320 KDa molecule consisting of a dimer of A subunits (FXIIIA2, 83 kDa) and a dimer of B subunits (FXIIIB2, 80 kDa)[1,2,3]
Unique to the FXIIIA subunit in the transglutaminase family is the presence of a 37 amino acid N-terminal activation peptide (FXIII-AP) which is cleaved by thrombin during Factor XIII (FXIII) activation
In order to understand the inter-residue relationships within the different parts of FXIIIA subunit and tissue transglutaminase-2 (TG2) plain molecular dynamics (MD) simulation was performed on the zymogenic human FXIIIA2 crystal structure (PDB ID: 1f13; 2.1 Å resolution)[24] and the zymogenic TG2 structure
Summary
The fibrin stabilizing factor or coagulation factor XIII (FXIII) is a heterotetrameric protein complex, circulating in the plasma as a 320 KDa molecule consisting of a dimer of A subunits (FXIIIA2, 83 kDa) and a dimer of B subunits (FXIIIB2, 80 kDa)[1,2,3]. The structure of calcium-activated and inhibitor-stabilized FXIIIA subunit (FXIIIAa) was solved which shows remarkable differences from the zymogenic form[26]. The primary targeted region for developing therapeutic inhibitors was the thrombin cleavage site and the catalytic triad in the zymogenic form of the FXIIIA subunit[33,34,35,36,37,38]. The activation of the FXIIIA2B2 heterotetramer in plasma is an elaborate process involving the cleavage of FXIII-AP by thrombin combined with calcium binding which causes large-scale conformational changes in the FXIIIA subunit structure and results in the dissociation of the FXIIIB subunits[26,39]. We compare observations and conclusions from the present study with results and conclusions derived from past literature
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