FOR 2509:  The concert of dolichol-based glycosylation: from molecules to disease models

• Subject Area: Biology
• Term: since 2017
• Website: Homepage
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 289991887

The covalent attachment of sugar units to proteins is a complex posttranslational modification found in all domains of life. N-glycosylation, C-mannosylation and O-mannosylation are prevalent and highly conserved glycosylation pathways, all essential for vertebrate development. The three pathways start in the endoplasmic reticulum, are based on the lipid dolichol and compete for both mannosyl donor substrates and acceptor proteins, which in many cases receive more than one type of glycan. Along these three glycosylation routes, today we know of endoplasmic reticulum associated defects in over 30 genes that cause devastating multisystemic disease manifestations (congenital disorders of glycosylation (CDG-I)), underlining the importance of these processes. So far, the three mentioned glycosylation pathways have been studied independently from each other. However, to understand the complexity of glycosylation disorders, it is imperative to decipher the details of the dolichol-based N-glycosylation, C- and O-mannosylation pathways, as well as the precise conditions for their interconnections. To address these questions on the molecular, cellular and organismal level, we have not only brought together experts in N-glycosylation, C- and O-mannosylation, but also in structural and lipid biochemistry, in proteomics, glycoproteomics, glycomics and lipidomics, as well as in developmental biology. In the frame of the collaborative Research Unit, we can thus make use of the newest methodological developments in the different fields. Our vision is to gain a deeper understanding of dolichol-based glycosylation to facilitate the development of diagnostic tools and new therapeutic approaches.

• DFG Programme: Research Units

Projects

• Characterization of induced pluripotent stem cell-based disease models for congenital disorders of glycosylation (Applicant Büttner, Falk )
• Complex formation, dolichol (re)cycling and pathological mechanisms in the initial steps of the N-glycosylation pathway (Applicant Thiel, Christian )
• Coordination Funds (Applicant Strahl, Sabine )
• Coordination Funds (Applicant Strahl, Sabine )
• Effects of glycosylation on protein structure, function and dynamics (Applicant Schwalbe, Harald )
• Effects of glycosylation on protein structure, function and dynamics (Applicant Schwalbe, Harald )
• Involvement of C-mannosylation in protein processing in the endoplasmic reticulum and implications for specific target proteins (Applicant Bakker, Hendrikus Hans )
• Monitoring the glycosylation network by quantitative mass spectrometry to study its functional and structural organization (Applicant Luzarowski, Marcin )
• Protein-lipid interactions and the influence of cellular lipid environments on glycosylation processes (Applicant Brügger, Britta )
• Protein O-mannosylation and its diverse interplay with N-glycosylation (Applicant Strahl, Sabine )
• Structural basis of protein O-mannosylation (Applicant Sinning, Irmgard )
• The role of ER-resident glycosylation in vertebrate neural development (Applicants Thumberger, Thomas ;  Wittbrodt, Joachim )
• Unravelling the correlation between different ER-based types of glycosylation via glyco/proteo-analytics (Applicant Rapp, Erdmann )
• Unravelling the correlation between different ER-based types of glycosylation via glyco/proteo-analytics (Applicant Rapp, Erdmann )

• Spokesperson: Professorin Dr. Sabine Strahl