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

Li, Bojun; Billur, Ramya; Maurer, Muriel C; Kohler, Hans-Peter; Raddatz Müller, Pascale; Alberio, Lorenzo; Schroeder, Verena (2018). Proline 36 of the Factor XIII Activation Peptide Plays a Crucial Role in Substrate Recognition and Zymogen Activation. Thrombosis and haemostasis, 118(12), pp. 2037-2045. Thieme 10.1055/s-0038-1675600

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The activation peptide of blood coagulation factor XIII (AP-FXIII) has important functions in stabilizing the FXIII-A 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 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 position still makes strong interactions with the active site cleft but the P-P residues (VVS) 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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Forschungsbereich Pavillon 52 > Forschungsgruppe Experimentelle Hämostase
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR)

UniBE Contributor:

Li, Bojun; Kohler, Hans-Peter and Schröder, Verena

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0340-6245

Publisher:

Thieme

Language:

English

Submitter:

Marla Rittiner

Date Deposited:

24 Jan 2019 15:50

Last Modified:

10 Dec 2019 16:13

Publisher DOI:

10.1055/s-0038-1675600

PubMed ID:

30419598

BORIS DOI:

10.7892/boris.122567

URI:

https://boris.unibe.ch/id/eprint/122567

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