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Rapid IgG heavy chain cleavage by the streptococcal IgG endopeptidase IdeS is mediated by IdeS monomers and is not due to enzyme dimerization
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
2013 (English)In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 587, no 12, 1818-1822 p.Article in journal (Refereed) Published
Abstract [en]

Streptococcus pyogenes employs an IgG specific endopeptidase, IdeS, to counteract the effector functions of specific IgG. The physiological significant step in disarming specific IgG is the cleavage of one IgG heavy chain. So far, characterizations of IdeS enzymatic activity have employed techniques that failed to differentiate between the first and the second cleavage step. The present data demonstrate that IdeS is active as a monomer and that IdeS activity follows classical Michaelis-Menten kinetics arguing against the previously proposed formation of a functional IdeS dimer. Our results show that IdeS inactivates IgG 100-fold faster than previously reported. (C) 2013 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Place, publisher, year, edition, pages
Elsevier, 2013. Vol. 587, no 12, 1818-1822 p.
Keyword [en]
IgG, Cysteine protease, Monomer/dimer, GAS, Virulence factor, Streptococcus pyogenes
National Category
Cell and Molecular Biology Microbiology in the medical area
URN: urn:nbn:se:umu:diva-78961DOI: 10.1016/j.febslet.2013.04.039ISI: 000320427400020OAI: diva2:638249
Available from: 2013-07-29 Created: 2013-07-29 Last updated: 2014-05-06Bibliographically approved
In thesis
1. Studies on secreted cysteine proteases of Streptococcus pyogenes: IdeS and SpeB
Open this publication in new window or tab >>Studies on secreted cysteine proteases of Streptococcus pyogenes: IdeS and SpeB
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The pathogen Streptococcus pyogenes is a significant cause of human morbidity and mortality. Most of the work in this thesis is focused on streptococcal virulence factor IdeS, but the thesis also features work on SpeB, another streptococcal virulence factor. Both IdeS and SpeB are secreted cysteine proteases and both have previously been shown to degrade human IgG. IgG is the only known substrate for IdeS while SpeB is a more promiscuous protease with a larger number of identified substrates. A significant part of the data presented in this thesis is the result of designing and optimizing methods to detect and accurately measure the proteolytic degradation of IgG. Methods aimed at measuring the binding interactions between enzyme and substrate have also been frequently utilized. I show that IdeS is a monomeric protease, as opposed to previously published data that suggested it to be dimeric. IdeS cleaves the two heavy chains of IgG in a two-step reaction and I demonstrate that the first cleavage is magnitudes faster than the second one. This means that IdeS is a more efficient enzyme than previously thought. The difference in rate cannot completely be explained by a loss of affinity between IdeS and IgG after the cleavage of the first heavy chain. The velocity of IdeS is further increased by the presence of human Cystatin C, via an unknown mechanism. Cystatin C is normally a protease inhibitor and it having an opposite effect is puzzling.The synthesis and evaluation of novel inhibitors are also described. Peptide analogues mimicking the sequence surrounding the scissile bond on IgG - with an amino acid replaced with a more rigid motif - act as specific, but low-affinity, inhibitors of IdeS. The peptide analogues’ inhibitory capacity for SpeB and papain was also assayed.When it comes to SpeB, I show that it does not have IgG as a substrate under physiological conditions, in contrast to what was previously thought. This thesis does not only present findings on the IgG degrading capacity of IdeS and SpeB but also include data on fundamental enzymatic properties for these proteases.

Place, publisher, year, edition, pages
Umeå: Umeå Universitet, 2014. 49 p.
Umeå University medical dissertations, ISSN 0346-6612 ; 1646
Streptococcus pyogenes, Group A Streptococci, GAS, virulence factor, IdeS, SpeB, cysteine protease, protease inhibitor, IgG, immune evasion
National Category
Biochemistry and Molecular Biology
Research subject
Molecular Biotechnology
urn:nbn:se:umu:diva-88223 (URN)978-91-7601-048-8 (ISBN)
Public defence
2014-05-27, Sal E04, by 6E, Norrlands universitetssjukhus, Umeå, 13:00 (English)
Available from: 2014-05-06 Created: 2014-04-28 Last updated: 2014-05-06Bibliographically approved

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Vindebro, ReineSpoerry, Christianvon Pawel-Rammingen, Ulrich
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