Publikationsserver der Universitätsbibliothek Marburg

Titel:Strukturelle und funktionelle Charakterisierung der epithelialen Adhäsine aus Candida glabrata
Autor:Diderrich, Rike
Weitere Beteiligte: Mösch, Hans-Ulrich (Prof. Dr.)
Veröffentlicht:2014
URI:https://archiv.ub.uni-marburg.de/diss/z2014/0352
DOI: https://doi.org/10.17192/z2014.0352
URN: urn:nbn:de:hebis:04-z2014-03521
DDC:570 Biowissenschaften, Biologie
Titel (trans.):Structural and functional characterization of epithelial adhesines of Candida glabrata
Publikationsdatum:2015-01-14
Lizenz:https://rightsstatements.org/vocab/InC-NC/1.0/

Dokument

Schlagwörter:
Candida glabrata, Adhäsine, Candida glabrata, Adhesine
Referenziert von:

Zusammenfassung:
Der humanpathogene Pilz Candida glabrata ist ein opportunistischer Erreger, der bevorzugt die Schleimhäute von Säugetieren besiedelt. C. glabrata ist für etwa 15 % der Blutstrominfektionen bei Menschen verantwortlich und verursacht besonders bei immunsupprimierten Patienten schwere Infektionsverläufe. Wichtige Virulenzfaktoren von C. glabrata sind die epithelialen Adhäsine (Epa-Proteine), von denen der Pilz je nach Stamm bis zu 23 verschiedene Mitglieder besitzt und die für die erfolgreiche Kolonisierung des Wirtes entscheidend sind. Die Epa-Proteine sind mit den Flokkulinen der Bäckerhefe Saccharomyces cerevisiae verwandt und gehören zu den Glycosylphosphatidylinositol-verankerten Zellwandproteinen (GPI-CWP). Sie besitzen eine typische, dreigeteilte Domänenstruktur, bei der die N-terminale A-Domäne für die Vermittlung der Adhäsion verantwortlich ist, die anschließende B-Domäne als Träger der A-Domäne fungiert und die C-terminale C-Domäne für die GPI-Verankerung in der Zellwand verantwortlich ist. Bisherige Untersuchungen an einigen Mitgliedern der Epa-Familie haben gezeigt, dass diese Adhäsine als Lektine fungieren und bestimmte Glykane auf der Oberfläche von Epithelzellen spezifisch erkennen und binden. Um die Struktur und Funktion der gesamten Epa-Protein-Familie im Detail zu untersuchen, wurden in dieser Arbeit alle 17 EpaA-Domänen des C. glabrata Stammes CBS138 heterolog hergestellt und aufgereinigt. Anschließend wurden Ligandenbindungsspezifitätsprofile aller 17 EpaA-Domänen über Glycan Array Screening ermittelt, wobei sich ergab, dass etwa 2/3 der Epa-Proteine Galactoside bevorzugen. Weiterhin wurden die exakten Bindungsstärken bestimmter EpaA-Domänen zu ausgewählten Glykan-Liganden ermittelt, die im niedrigen mikromolaren Bereich liegen. Ebenso gelang auch die Strukturlösung von Epa6A und Epa9A mit verschiedenen Liganden. Dadurch konnten sowohl konservierte als auch variable Aminosäurereste identifiziert werden, die für die Affinität und Spezifität wichtig sind und die anschließend über gezielte Mutagenese genauer untersucht wurden.Um die Funktion der EpaA-Domänen auch systematisch in vivo zu untersuchen und mit den biochemische Ergebnissen zu vergleichen, wurden 15 der EpaA-Domänen in einem heterologen Expressionssystem einzeln an die Zelloberfläche von S. cerevisiae gebracht und deren Fähigkeit zur Adhäsionsvermittlung an menschliche Epithelzellen und abiotische Oberflächen bestimmt. Zusammenfassend gibt diese Arbeit einen detaillierten Einblick in die Struktur und Funktion einer kompletten Multiprotein-Familie, wobei die präzise Charakterisierung der Ligandenbindungsstellen von besonderem Interesse ist, da diese für die Pathogenität von C. glabrata entscheidend sind und als mögliche Ziele für die zukünftige Entwicklung dringend benötigter, neuer Antimykotika in Frage kommen.

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