Role of the activation peptide in the mechanism of protein C activation

Abstract Protein C is a natural anticoagulant activated by thrombin in a reaction accelerated by the cofactor thrombomodulin. The zymogen to protease conversion of protein C involves removal of a short activation peptide that, relative to the analogous sequence present in other vitamin K-dependent p...

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Autores principales:	Bosko M. Stojanovski, Leslie A. Pelc, Enrico Di Cera
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/21d2d7669254469895a25cc38ee0ab1c
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spelling	oai:doaj.org-article:21d2d7669254469895a25cc38ee0ab1c2021-12-02T15:39:40ZRole of the activation peptide in the mechanism of protein C activation10.1038/s41598-020-68078-z2045-2322https://doaj.org/article/21d2d7669254469895a25cc38ee0ab1c2020-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-68078-zhttps://doaj.org/toc/2045-2322Abstract Protein C is a natural anticoagulant activated by thrombin in a reaction accelerated by the cofactor thrombomodulin. The zymogen to protease conversion of protein C involves removal of a short activation peptide that, relative to the analogous sequence present in other vitamin K-dependent proteins, contains a disproportionately high number of acidic residues. Through a combination of bioinformatic, mutagenesis and kinetic approaches we demonstrate that the peculiar clustering of acidic residues increases the intrinsic disorder propensity of the activation peptide and adversely affects the rate of activation. Charge neutralization of the acidic residues in the activation peptide through Ala mutagenesis results in a mutant activated by thrombin significantly faster than wild type. Importantly, the mutant is also activated effectively by other coagulation factors, suggesting that the acidic cluster serves a protective role against unwanted proteolysis by endogenous proteases. We have also identified an important H-bond between residues T176 and Y226 that is critical to transduce the inhibitory effect of Ca2+ and the stimulatory effect of thrombomodulin on the rate of zymogen activation. These findings offer new insights on the role of the activation peptide in the function of protein C.Bosko M. StojanovskiLeslie A. PelcEnrico Di CeraNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-10 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Bosko M. Stojanovski Leslie A. Pelc Enrico Di Cera Role of the activation peptide in the mechanism of protein C activation
description	Abstract Protein C is a natural anticoagulant activated by thrombin in a reaction accelerated by the cofactor thrombomodulin. The zymogen to protease conversion of protein C involves removal of a short activation peptide that, relative to the analogous sequence present in other vitamin K-dependent proteins, contains a disproportionately high number of acidic residues. Through a combination of bioinformatic, mutagenesis and kinetic approaches we demonstrate that the peculiar clustering of acidic residues increases the intrinsic disorder propensity of the activation peptide and adversely affects the rate of activation. Charge neutralization of the acidic residues in the activation peptide through Ala mutagenesis results in a mutant activated by thrombin significantly faster than wild type. Importantly, the mutant is also activated effectively by other coagulation factors, suggesting that the acidic cluster serves a protective role against unwanted proteolysis by endogenous proteases. We have also identified an important H-bond between residues T176 and Y226 that is critical to transduce the inhibitory effect of Ca2+ and the stimulatory effect of thrombomodulin on the rate of zymogen activation. These findings offer new insights on the role of the activation peptide in the function of protein C.
format	article
author	Bosko M. Stojanovski Leslie A. Pelc Enrico Di Cera
author_facet	Bosko M. Stojanovski Leslie A. Pelc Enrico Di Cera
author_sort	Bosko M. Stojanovski
title	Role of the activation peptide in the mechanism of protein C activation
title_short	Role of the activation peptide in the mechanism of protein C activation
title_full	Role of the activation peptide in the mechanism of protein C activation
title_fullStr	Role of the activation peptide in the mechanism of protein C activation
title_full_unstemmed	Role of the activation peptide in the mechanism of protein C activation
title_sort	role of the activation peptide in the mechanism of protein c activation
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/21d2d7669254469895a25cc38ee0ab1c
work_keys_str_mv	AT boskomstojanovski roleoftheactivationpeptideinthemechanismofproteincactivation AT leslieapelc roleoftheactivationpeptideinthemechanismofproteincactivation AT enricodicera roleoftheactivationpeptideinthemechanismofproteincactivation
_version_	1718385859521150976

Role of the activation peptide in the mechanism of protein C activation

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