umu.sePublikationer
Ändra sökning
RefereraExporteraLänk till posten
Permanent länk

Direktlänk
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Annat format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annat språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf
Rapid IgG heavy chain cleavage by the streptococcal IgG endopeptidase IdeS is mediated by IdeS monomers and is not due to enzyme dimerization
Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
2013 (Engelska)Ingår i: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 587, nr 12, s. 1818-1822Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
Elsevier, 2013. Vol. 587, nr 12, s. 1818-1822
Nyckelord [en]
IgG, Cysteine protease, Monomer/dimer, GAS, Virulence factor, Streptococcus pyogenes
Nationell ämneskategori
Cell- och molekylärbiologi Mikrobiologi inom det medicinska området
Identifikatorer
URN: urn:nbn:se:umu:diva-78961DOI: 10.1016/j.febslet.2013.04.039ISI: 000320427400020OAI: oai:DiVA.org:umu-78961DiVA, id: diva2:638249
Tillgänglig från: 2013-07-29 Skapad: 2013-07-29 Senast uppdaterad: 2018-06-08Bibliografiskt granskad
Ingår i avhandling
1. Studies on secreted cysteine proteases of Streptococcus pyogenes: IdeS and SpeB
Öppna denna publikation i ny flik eller fönster >>Studies on secreted cysteine proteases of Streptococcus pyogenes: IdeS and SpeB
2014 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Umeå: Umeå Universitet, 2014. s. 49
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 1646
Nyckelord
Streptococcus pyogenes, Group A Streptococci, GAS, virulence factor, IdeS, SpeB, cysteine protease, protease inhibitor, IgG, immune evasion
Nationell ämneskategori
Biokemi och molekylärbiologi
Forskningsämne
molekylär bioteknik (inst f molekylärbiologi)
Identifikatorer
urn:nbn:se:umu:diva-88223 (URN)978-91-7601-048-8 (ISBN)
Disputation
2014-05-27, Sal E04, by 6E, Norrlands universitetssjukhus, Umeå, 13:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2014-05-06 Skapad: 2014-04-28 Senast uppdaterad: 2018-06-07Bibliografiskt granskad
2. Streptococcal immunoglobulin degrading enzymes of the IdeS and IgdE family
Öppna denna publikation i ny flik eller fönster >>Streptococcal immunoglobulin degrading enzymes of the IdeS and IgdE family
2017 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Bacteria of the genus Streptococcus are common asymptomatic colonisers of humans and animals. As opportunistic pathogens they can however, depending on their host’s immune status and other circumstances, cause mild to very severe infections. Streptococci are highly intertwined with specific host species, but can also cause zoonosis or anthroponosis in more uncommon hosts. Prolonged and reoccurring infections require immune evasion strategies to circumvent detection and eradication by the host’s immune defence. A substantial part of the immune defence against bacterial pathogens is mediated by immunoglobulins. This thesis is based on work to identify and characterise immunoglobulin degrading enzymes secreted by different Streptococcus species as a means to sabotage and evade antibody-mediated immune responses.

Stoichiometric and kinetic analysis of the IgG degrading enzyme IdeS from the important human pathogen S. pyogenes revealed that IdeS cleaves IgG, opposed to previous publications, as a monomer following classical Michaelis-Menten kinetics.

The IdeS homologue of S. suis, IdeSsuis, did however not cleave IgG, but was highly specific fo rporcine IgM. S. suis was found to possess yet another protease, IgdE, capable of cleaving porcine IgG. Both of these proteases were shown to promote increased bacterial survival in porcine blood during certain conditions.

IgdE is the founding member of a novel cysteine protease family (C113). Novel streptococcal members of this protease family were shown to specifically degrade certain IgG subtypes of the respective Streptococcus species’ main host. The observed substrate specificity of IgdE family proteases reflects the host tropism of these Streptococcus species, thereby giving insights into host-pathogen co-evolution.

The abundance of immunoglobulin degrading enzymes among Streptococcus species indicates the importance of evasion from the antibody mediated immune responses for streptococci. These novel identified immunoglobulin degrading enzymes of the IdeS and IgdE protease families are potential valid vaccine targets and could also be of biotechnological use.

Ort, förlag, år, upplaga, sidor
Umeå: Umeå universitet, 2017. s. 61
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 1892
Nyckelord
Streptococcus, S. pyogenes, S. agalactiae, S. suis, S. porcinus, S. pseudoporcinus, S. equi subsp. zooepidemicus, protease, immunoglobulin, immune evasion, IdeS, IgdE
Nationell ämneskategori
Cell- och molekylärbiologi Biokemi och molekylärbiologi
Forskningsämne
molekylärbiologi
Identifikatorer
urn:nbn:se:umu:diva-134552 (URN)9789176016985 (ISBN)
Disputation
2017-06-01, Major Groove, Byggnad 6L, Norrlands Universitetssjukhus, Umeå, 13:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2017-05-11 Skapad: 2017-05-08 Senast uppdaterad: 2018-06-09Bibliografiskt granskad

Open Access i DiVA

Fulltext saknas i DiVA

Övriga länkar

Förlagets fulltext

Personposter BETA

Vindebro, ReineSpoerry, Christianvon Pawel-Rammingen, Ulrich

Sök vidare i DiVA

Av författaren/redaktören
Vindebro, ReineSpoerry, Christianvon Pawel-Rammingen, Ulrich
Av organisationen
Institutionen för molekylärbiologi (Medicinska fakulteten)
I samma tidskrift
FEBS Letters
Cell- och molekylärbiologiMikrobiologi inom det medicinska området

Sök vidare utanför DiVA

GoogleGoogle Scholar

doi
urn-nbn

Altmetricpoäng

doi
urn-nbn
Totalt: 213 träffar
RefereraExporteraLänk till posten
Permanent länk

Direktlänk
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Annat format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annat språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf