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The human protease inhibitor cystatin C is an activating cofactor for the streptococcal cysteine protease IdeS
Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). (Pawel)
Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). (Pawel)
2008 (engelsk)Inngår i: Chemistry and Biology, ISSN 1074-5521, E-ISSN 1879-1301, Vol. 15, nr 9, s. 960-968Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Human cystatin C is considered the physiologically most important inhibitor of endogenous papain-like cysteine proteases. We present here an unexpected function of cystatin C. Instead of acting as an inhibitor, cystatin C acts as a facultative, endogenous cofactor for the papain-like IgG-cleaving enzyme IdeS of the human pathogen Streptococcus pyogenes. IdeS activity is not dependent on cystatin C, but is significantly enhanced in the presence of cystatin C. We report a protease inhibitor that accelerates the activity of its putative target protease and a unique example of how a host protease inhibitor is "hijacked" by a bacterial protease to increase its activity. This finding has important implications for the view on protease-inhibitor interactions, and is relevant to consider in the therapeutic use of protease inhibitors.

sted, utgiver, år, opplag, sider
2008. Vol. 15, nr 9, s. 960-968
Emneord [en]
Chembio; microbio; proteins
HSV kategori
Identifikatorer
URN: urn:nbn:se:umu:diva-20793DOI: 10.1016/j.chembiol.2008.07.021ISI: 000259918200011PubMedID: 18804033OAI: oai:DiVA.org:umu-20793DiVA, id: diva2:209562
Tilgjengelig fra: 2009-03-25 Laget: 2009-03-25 Sist oppdatert: 2018-06-09bibliografisk kontrollert
Inngår i avhandling
1. Studies on secreted cysteine proteases of Streptococcus pyogenes: IdeS and SpeB
Åpne denne publikasjonen i ny fane eller vindu >>Studies on secreted cysteine proteases of Streptococcus pyogenes: IdeS and SpeB
2014 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
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.

sted, utgiver, år, opplag, sider
Umeå: Umeå Universitet, 2014. s. 49
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 1646
Emneord
Streptococcus pyogenes, Group A Streptococci, GAS, virulence factor, IdeS, SpeB, cysteine protease, protease inhibitor, IgG, immune evasion
HSV kategori
Forskningsprogram
molekylär bioteknik (inst f molekylärbiologi)
Identifikatorer
urn:nbn:se:umu:diva-88223 (URN)978-91-7601-048-8 (ISBN)
Disputas
2014-05-27, Sal E04, by 6E, Norrlands universitetssjukhus, Umeå, 13:00 (engelsk)
Opponent
Veileder
Tilgjengelig fra: 2014-05-06 Laget: 2014-04-28 Sist oppdatert: 2018-06-07bibliografisk kontrollert

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