Proline 36 of the Factor XIII Activation Peptide Plays a Crucial Role in Substrate Recognition and Zymogen Activation.

Détails

ID Serval
serval:BIB_07B5E48E31DA
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Proline 36 of the Factor XIII Activation Peptide Plays a Crucial Role in Substrate Recognition and Zymogen Activation.
Périodique
Thrombosis and haemostasis
Auteur(s)
Li B., Billur R., Maurer M.C., Kohler H.P., Raddatz Müller P., Alberio L., Schroeder V.
ISSN
2567-689X (Electronic)
ISSN-L
0340-6245
Statut éditorial
Publié
Date de publication
12/2018
Peer-reviewed
Oui
Volume
118
Numéro
12
Pages
2037-2045
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: ppublish
Résumé
The activation peptide of blood coagulation factor XIII (AP-FXIII) has important functions in stabilizing the FXIII-A <sub>2</sub> dimer and regulating FXIII activation. Contributions of many of its 37 amino acids to these functions have been described. However, the role of proline 36, which is adjacent to the thrombin cleavage site at Arg37, has not yet been studied in detail. We approached this question when we came across a patient with congenital FXIII deficiency in whom we detected a novel Pro36Ser mutation. We expressed the mutant FXIII-A Pro36Ser protein in Chinese hamster ovary cells and found that this mutation does not influence FXIII-A expression but significantly inhibits proteolytic activation by thrombin. The enzymatic transglutaminase activity is not affected as it can be induced in the presence of high Ca <sup>2+</sup> concentrations. We performed nuclear magnetic resonance analysis to investigate AP-FXIII-thrombin interactions, which showed that the mutant Ser36 peptide binds less well to the thrombin surface than the native Pro36 peptide. The Arg37 at the P <sub>1</sub> position still makes strong interactions with the active site cleft but the P <sub>4</sub> -P <sub>2</sub> residues ( <sup>34</sup> VVS <sup>36</sup> ) appear to be less well positioned to contact the neighbouring thrombin active site region. In conclusion, we have characterized a novel mutation in AP-FXIII representing only the fourth case of the rare FXIII-A type II deficiency. This case served as a perfect in vivo model to shed light on the crucial role of Pro36 in the proteolytic activation of FXIII-A. Our results contribute to the understanding of structure-function relationship in FXIII.
Mots-clé
Animals, CHO Cells, Cricetulus, Enzyme Precursors/metabolism, Factor XIII/genetics, Factor XIII/metabolism, Factor XIII Deficiency/genetics, Humans, Mutation/genetics, Peptides/genetics, Peptides/metabolism, Proline/genetics, Protein Binding/genetics, Proteolysis, Structure-Activity Relationship, Substrate Specificity, Thrombin/metabolism
Pubmed
Web of science
Création de la notice
19/11/2018 13:48
Dernière modification de la notice
20/08/2019 12:30
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