Spacer
Scientist (f/m) / PhD position Protein O-mannosylation and its diverse interplay with N-glycosylation
Description:
Protein O-mannosylation and N-glycosylation are fundamental processes that are essential for the growth and development of eukaryotes. 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, the congenital disorders of glycosylation (CDGs). 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 fundamental questions, we 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. Our analyses will provide a comprehensive view of the initiation of O-mannosylation as well as the diverse implications of O-mannosylation defects, and guide the analyses of physio-pathologic abnormalities in CDG models.

 

References: Neubert P, Strahl S. (2016) Protein O-mannosylation in the early secretory pathway. Curr Opin Cell Biol. 41:100-8. doi: 10.1016/j.ceb.2016.04.010. Bartels MF, Winterhalter PR, Yu J, Liu Y, Lommel M, Möhrlen F, Hu H, Feizi T, Westerlind U, Ruppert T and Strahl S. (2016) Protein O-Mannosylation in the Murine Brain: Occurrence of Mono-O-Mannosyl Glycans and Identification of New Substrates. PLoS One. 11:e0166119. doi: 10.1371/journal.pone.0166119. Carvalho, S, Oliveira, T, Bartels, MF, Miyoshi, E, Pierce, M, Taniguchi, N, Carneiro, F, Seruca, R, Reis, CA, Strahl, S and Pinho, SS (2016). O–mannosylation and N-glycosylation: two coordinated mechanisms regulating the tumour suppressor functions of E-cadherin in cancer. Oncogene. DOI: 10.18632/oncotarget.11245. Bausewein D, Engel J, Jank T, Schoedl, M and Strahl, S (2016). Functional similarities between the protein O-mannosyltransferases Pmt4 from baker's yeast and human POMT1. J Biol Chem. DOI:10.1074/jbc.M116.739128. Ragni, E, Lommel, M, Moro, M, Crosti, M, Lavazza, C, Parazzi, V, Saredi S, Strahl, S and Lazzari, L (2016). Protein O-mannosylation is crucial for human mesencyhmal stem cells fate. Cell Mol Life Sci. 7. :445-58. Loibl, M, Wunderle, L, Hutzler, J, Schulz, BL, Aebi, M and Strahl, S (2014). Protein O-mannosyltransferases associate with the translocon to modify translocating polypeptide chains. J Biol Chem. 289, 8599-611. Lommel, M, Winterhalter, PR, Willer, T, Dahlhoff, M, Schneider, MR, Bartels, MF, Renner-Müller, I, Ruppert, T, Wolf, E and Strahl, S (2013). Protein O-mannosylation is crucial for E-cadherin-mediated cell adhesion. Proc Natl Acad Sci U S A. 110, 21024-9. Methods that will be used: Analysis of cell culture and medaka fish CDG models. Molecular biology, CRISPR/Cas9, cell biology, real-time cell analysis, FACS, protein biochemistry, cell free translation/ translocation/ glycosylation, mannosyltransferase activity assays, lectins, transcriptomics, label-free and SILAC-based proteomics, glycoproteomics and glycomics. Cooperation partners: Prof. Dr. Britta Brügger (BZH, Heidelberg University), Prof. Dr. Irmgard Sinning (BZH, Heidelberg University), Dr. Erdmann Rapp (MPI Magdeburg), Dr. Thomas Ruppert (ZMBH, Heidelberg University), PD Dr. Christian Thiel (University Hospital Heidelberg), Prof. Dr. Joachim Wittbrodt (COS, Heidelberg University), Jun. Prof. Dr. Falk Büttner and Dr. Hans Bakker (MHH, Hannover)

Personal qualifications: Applicants should hold an excellent Master/PhD degree in Biology, Biochemistry, Molecular Cell Biology or comparable topics. The successful candidate should have a very high level of motivation to perform creative basic research. Candidates should be true team players, have good communication skills and good knowledge of the English language. Experience in human/animal cell culture, molecular and cell biology, protein biochemistry and/or glycobiology is preferred. The position will require attention to detail, strong skills in experimental design and troubleshooting, and an ability to pursue research projects independently

 

Deadline: 18. Jun 2017

 

Contact details: Strahl, Sabine