Protein quality control and aging

1 PhD project in the IPP summer call 2018

Scientific Background

Protein quality control systems maintain a functional proteome through detection and removal of abnormal proteins. While typically only misfolded or damaged molecules are thought of as abnormal, recent work – including our own (Khmelinskii et al. 2014) – revealed that also mislocalized proteins are subject to quality control. Mislocalized proteins are defined as proteins that fail to reach their native compartment or fail to assemble into their native complex, and thus cannot function normally. Protein mislocalization is a constitutive problem caused by inherent inefficiencies of cellular processes and increases with aging. Proteins can also mislocalize due to mutations, as seen in various metabolic, cardiovascular and neurodegenerative diseases, and some types of cancer. Thus, understanding how cells deal with mislocalized proteins is not only important from the point of view of basic research but will also contribute to elucidating causes of diseases at the molecular level.

PhD project proposal: Quality control of mislocalized proteins

In this project we will dissect quality control mechanisms of mislocalized proteins through a combination of high-throughput screening, molecular biology, genetics and biochemistry. We will take advantage of powerful yeast genetics and a proteome-wide platform for conditional protein mislocalization to screen for machinery involved in quality control of different types of mislocalized proteins, to understand how cells recognize mislocalized proteins as abnormal and to investigate the roles of such quality control systems in the aging process.

We are looking for a highly motivated individual with a degree in Molecular Biology, Biochemistry, Biotechnology or related fields. The successful candidate will join an enthusiastic team and combine genetic screening approaches with proteomics, biochemistry and molecular biology techniques to uncover general principles of protein quality control. Excellent core facilities in the institute will provide the necessary support with mass spectrometry, sequencing and flow cytometry requirements of the project.

Publications relevant to the project

Meurer M, Duan Y, Sass E, Kats I, Herbst K, Buchmuller BC, Dederer V, Huber F, Kirrmaier D, Stefl M, Van Laer K, Dick TP, Lemberg MK, Khmelinskii A, Levy ED, 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, Knop M (2018) Mapping degradation signals and pathways in a eukaryotic N-terminome. Molecular 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

Khmelinskii A, Keller PJ, Bartosik A, Meurer M, Barry JD, Mardin BR, Kaufmann A, Trautmann S, Wachsmuth M, Pereira G, Huber W, Schiebel E, Knop M (2012) Tandem fluorescent protein timers for in vivo analysis of protein dynamics. Nature Biotechnology 30:708-14


Contact Details

Dr Anton Khmelinskii