Project (Sonja Lorenz)
Exploring the mechanisms of how the ubiquitin system controls protein synthesis

The Quantitative and Systems Biology group employs in silico approaches, using in vitro and ex vivo and in vivo experimental data, to study the pathways of the proteasome that regulate the human immune response.
Our research group is fascinated by the question of how protein modifiers of the ubiquitin family regulate countless physiological and pathophysiological pathways with astounding specificity. A major key lies in the action of ubiquitin ligases, the most diversified class of enzymes in the ubiquitin system with powerful therapeutic potential. However, progress towards rationally manipulating these enzymes has been impeded largely by our insufficient understanding of their conformational dynamics, macromolecular interactions, and functional integration into cellular pathways. Emerging evidence suggests that ubiquitin ligases crosstalk with the ribosome, both structurally and functionally, thereby controlling protein synthesis, turnover, and ribosome homeostasis. We offer a fully-funded PhD student position to explore the underlying mechanisms of this crosstalk. In particular, we are looking to recruit a candidate with a dedicated interest - and ideally some prior expertise - in mammalian cell biology and/or proteomic approaches. In our studies, we colllaborate closely with the laboratories of Marina Rodnina (ribosome mechanisms) and Henning Urlaub (mass spectrometry) at the MPI NAT Goettingen.

• Sander B, Xu W, Eilers M, Popov N, Lorenz S (2017). A conformational switch regulates the ubiquitin ligase HUWE1. eLife 6: e21036.
  
• Lorenz S (2017). Structural mechanisms of HECT-type ubiquitin ligases. Biol Chem 399: 127-145.
  
• Chen D, Gehringer M, Lorenz S (2018) Developing small-molecule inhibitors of HECT-type ubiquitin ligases for therapeutic applications: challenges and opportunities. ChemBioChem 19: 2123-2135.
  
• Ries LK, Sander B, Deol KK, Letzelter MA, Strieter ER, Lorenz S (2019). Analysis of ubiquitin recognition by the HECT ligase E6AP provides insight into its linkage specificity. J Biol Chem 294: 6113-6129
  
• Liess A*, Kucerova A*, Schweimer K, Yu L, Roumeliotis T, Diebold M, Dybkov O, Sotriffer C, Urlaub H, Choudhary J, Mansfeld J#, Lorenz S# (2019). Auto-inhibition mechanism of the ubiquitin-conjugating enzyme UBE2S by auto-ubiquitination. Structure 27:1195-1210 - featured in Bodrug T, Brown NG (2019). UBE2S learns self control. Structure 27: 11185-1187.
  
• Liess AKL*, Kucerova A*, Schweimer K, Schlesinger D, Dybkov O, Urlaub H, Mansfeld J#, and Lorenz S#: Dimerization regulates the human APC/C-associated ubiquitin-conjugating enzyme UBE2S. Sci Signal 13:eaba8208 - featured in: Bremm A. (2020) Hug and hold tight: Dimerization controls the turnover of the ubiquitin-conjugating enzyme UBE2S. Sci Signal 13:eabd9892.
  
• Nair RM, Seenivasan A, Liu B, Chen D, Lowe ED, Lorenz S (2021) Reconstitution and structural analysis of a HECT ligase-ubiquitin complex via an activity-based probe. ACS Chem Biol. 16: 1615-1621.