Specificity in selective protein degradation

Scientific Background

Proteome integrity is maintained by a complex proteostasis network that controls protein synthesis, folding, transport and degradation. Numerous protein quality control systems that operate throughout the protein lifecycle contribute to proteome homeostasis through prevention, detection and removal of abnormal proteins. Nevertheless, proteome homeostasis declines with ageing and in numerous diseases, resulting in accumulation of abnormal proteins and loss of cell functionality. We aim to systematically examine how cells deal with different types of abnormal proteins. Working in yeast and human cells, we employ high-throughput genetic and proteomic assays in combination with cell/molecular biology and biochemical approaches to elucidate how cells identify abnormal proteins and to explore links between protein quality control, cancer and ageing.

The Project

Selective protein degradation by the ubiquitin-proteasome system (UPS) plays a key role in proteome turnover and quality control. Using proteomic approaches, we have recently examined the contributions of different UPS components, including most E3 ubiquitin ligases and deubiquitinating enzymes (DUBs), to yeast proteome turnover (Kong et al. 2021). This work yielded potential substrates and functions for many E3s and DUBs. We are seeking to recruit an outstanding candidate to build and expand upon these efforts to address a key question: how does each E3 or DUB recognize its substrates? The successful candidate will join a highly motivated international team and develop an interdisciplinary project, combining deep mutational scanning, phage display, biochemical and computational analyses, to systematically dissect specificity determinants in the UPS. With strong support for genomics and proteomics from IMB Core Facilities, the project is aimed at systematically identifying degradation signals (degrons) recognized by different UPS components and uncovering functions of such degron motifs in disease.

Candidates are requested to submit a 1-page cover letter explaining the reasons to join our group, a concise project proposal, curriculum vitae and 2 references.

Requirements of the candidate

  • PhD in cell biology, molecular biology, genetics, systems biology or a related field
  • Extensive experience with budding yeast and high-throughput yeast genetics
  • Experience with genetic screens and deep mutational scanning
  • Excellent organization skills and the ability to work independently
  • Work experience in interdisciplinary teams
  • Excellent communication skills in English

Publications Relevant to the Project

Kong KE*, Fischer B*, Meurer M*, Kats I, Li Z, Rühle F, Barry JD, Kirrmaier D, Chevyreva V, San Luis BJ, Costanzo M, Huber W, Andrews BJ, Boone C, Knop M#, Khmelinskii A# (2021) Timer-based proteomic profiling of the ubiquitin-proteasome system reveals a substrate receptor of the GID ubiquitin ligase. Mol Cell, 81:2460-2476.

Meurer M*, Duan Y*, Sass E*, Kats I, Herbst K, Buchmuller BC, Dederer V, Huber F, Kirrmaier D, Štefl M, Van Laer K, Dick TP, Lemberg MK, Khmelinskii A#, Levy ED# and Knop M# (2018) Genome-wide C-SWAT library for high-throughput yeast genome tagging. Nature Methods, 15: 598-600.

Kats I, Khmelinskii A, Kschonsak M, Huber F, Knieß RA, Bartosik A and Knop M (2018) Mapping degradation signals and pathways in a eukaryotic N-terminome. Mol Cell, 70: 488-501.

Khmelinskii A*, Blaszczak E*, Pantazopoulou M, Fischer B, Omnus DJ, Le Dez G, Brossard A, Gunnarsson A, Barry JD, Meurer M, Kirrmaier D, Boone C, Huber W, Rabut G*, Ljungdahl PO*, Knop M* (2014) Protein quality control at the inner nuclear membrane. Nature 516:410-3.

More Details

Dr Anton Khmelinskii

Research website