The folding of newly synthesized proteins is particularly vulnerable and therefore secured by multiple chaperone machineries that promote co-translational folding and assembly of protein complexes. Recent findings suggest that folding is furthermore controlled by the translation process itself, through ribosomal pausing during translation elongation. Our research aims at understanding the molecular mechanisms of chaperone-assisted folding and assembly of proteins to the native state in eukaryotes. Moreover, we want to understand how certain mutations in the decoded open reading frame and in chaperone genes affect these processes. Ribosome profiling (RP; the deep-sequencing of ribosome protected mRNA fragments) has emerged as a novel method to quantitatively assess translation in living cells, providing proteome-wide measures of translation regulation, local elongation kinetics and spatial coordination of protein synthesis. The recent extension of the RP technique by us now allows to uncover genome-wide co-translational interactions of nascent polypeptides that guide protein folding, membrane targeting and protein complex assembly and how these processes are coordinated with translation. The proposed project will use RP and bioinformatics tools to analyze high-throughput deep-sequencing data to study the complex interplay of translation with maturation processes of nascent proteins.
Relevant publications:
Schibich D, Gloge F, Pöhner I, Björkholm P, Wade RC, von Heijne G, Bukau B, Kramer G. Global profiling of SRP interaction with nascent polypeptides. (2016). Nature 536:219-23. Shieh, Y.-W., Minguez, P., Bork, P., Auburger, J.J., Guilbride, D.L., Kramer, G., Bukau, B.: Operon structure and cotranslational subunit association direct protein assembly in bacteria. (2015) Science 350, 678-680. Oh, E., Becker, A.H., Sandikci, A., Huber, D., Chaba, R., Gloge, F., Nichols, R.J., Typas, A., Gross, C.A., Kramer, G., Weissman, J.S., Bukau, B. Selective ribosome profiling reveals the cotranslational chaperone action of trigger factor in vivo. (2011) Cell 147, 1295-1308.
Reviews:
Kramer, G., Boehringer, D., Ban, N., Bukau, B. The ribosome as a platform for co-translational processing, folding and targeting of newly synthesized proteins. Nat. Struct. Mol. Biol. (2009) 16, 589-597. Gloge, F., Becker, A.H., Kramer, G., Bukau, B. Co-translational mechanisms of protein maturation. (2013) Curr. Opin. Struct. Biol. 24, 24-33.
back to main