Project Details
Projekt
Protein O-mannosylation and its diverse interplay with N-glycosylation
Applicant
Professorin Dr. Sabine Strahl
Subject Area
Biochemistry
Term
since 2017
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 289991887
Protein O-mannosylation and N-glycosylation are fundamental processes that are essential for the growth and development of eukaryotes. Both protein modifications initiate at the endoplasmic reticulum, where the synthesis of the donor saccharides and the covalent coupling of the carbohydrate moiety and the polypeptide occur. Properly glycosylated and folded proteins can journey on to the Golgi apparatus where N-linked and O-mannosyl glycans are further trimmed and/or elongated. Ultimately, glycoproteins with highly diverse glycans emerge that in turn allow dynamic adaptations to developmental and environmental changes. The importance of these protein modifications becomes obvious in light of the fact that defects in both types of glycosylation result in severe human diseases such as the congenital disorders of glycosylation (CDGs).In the endoplasmic reticulum, the N-glycosylation machinery and protein O-mannosyltransferases compete for the sugar donor dolichol phosphate-activated mannose. There is now growing evidence that the connection between O-mannosylation and N-glycosylation extends far beyond their sharing of a common sugar donor. We showed that, in baker´s yeast, O-mannosylation can be initiated at the Sec61 translocon complex and yeast O-mannosyltransferases can indeed compete for N-glycosylation acceptor sites. Whether mammalian O-mannosyltransferases also act at the translocon complex, potentially interfering with the initiation of N-glycosylation, has not so far been addressed. Furthermore, our recent work revealed that the inhibition of mammalian protein O-mannosyltransferases negatively affects E-cadherin-mediated cell-cell adhesion, via unexpected crosstalk between O-mannosylation and the biosynthesis of individual N-glycan structures on this important adhesion molecule. It is still unclear, however, whether the observed effect is restricted to E-cadherin or whether N-glycosylation is generally affected by a decrease in O-mannosylation, and what mechanisms are behind this coordinated interplay.To address these questions, we now aim to study mammalian O-mannosylation and its relation to N-glycosylation at the operating, regulatory and functional levels. Our main objectives are i) to unravel the mode of action of the mammalian O-mannosyltransferases in the endoplasmic reticulum; and ii) to explain the consequences of defective O-mannosylation at the molecular level with a focus on cadherins.In combination, our analyses will provide a comprehensive view of the initiation of O-mannosylation in the endoplasmic reticulum as well as the diverse implications of O-mannosylation defects, and guide the analyses of physio-pathologic abnormalities in CDG models.
DFG Programme
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