Ruprecht-Karls-Universität Heidelberg
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Mogk0118 - Scientist (f/m) / PhD position
Project no:

Project leader:

Project supervisor:
Mogk, Axel
Application deadline:
30. Sep 2018
Start of PhD project:
1. Nov 2018

Project description:

Structural and mechanistic basis of stand-alone disaggregase conferring superior heat resistance
Environmental stress conditions cause protein misfolding and ultimately protein aggregation. The reactivation of aggregated proteins by molecular chaperones is essential for the survival of cells during severe heat stress. Heat resistance is provided by AAA+ disaggregases, which represent ring-forming machines that remove polypeptides from protein aggregates by an ATP-driven threading activity. The classical disaggregase ClpB needs to cooperate with an Hsp70 partner chaperone during disaggregation for targeting to protein aggregates and stimulation of its ATPase activity. We recently identified a novel AAA+ disaggregase, ClpG, which does not require assistance by Hsp70 and functions as stand-alone disaggregase. ClpG confers superior heat resistance to bacteria, which is becoming an increasingly important virulence factor promoted by modern food production and medical sterilization procedures involving heat treatment.
The project aims at the detailed mechanistic understanding of ClpG disaggregation activity. How does ClpG recognize protein aggregates? How is the binding event linked to control of ATPase and threading activities? How does ClpG cooperate with evolutionary co-organized chaperones? The study will provide important insights into disaggregase function and can provide basis for rationale drug design.
Lee C, Franke KB, Kamal SM, Kim H, Lunsdorf H, Jager J, Nimtz M, Trcek J, Jansch L, Bukau B, Mogk A, Romling U (2018) Stand-alone ClpG disaggregase confers superior heat tolerance to bacteria. Proc Natl Acad Sci U S A 115: E273-E282

Mogk A, Bukau B, Kampinga HH (2018) Cellular Handling of Protein Aggregates by Disaggregation Machines. Mol Cell 69: 214-226

Carroni M, Franke KB, Maurer M, Jager J, Hantke I, Gloge F, Linder D, Gremer S, Turgay K, Bukau B, Mogk A (2017) Regulatory coiled-coil domains promote head-to-head assemblies of AAA+ chaperones essential for tunable activity control. eLife 6

Lee C, Wigren E, Lunsdorf H, Romling U (2016) Protein homeostasis-more than resisting a hot bath. Curr Opin Microbiol 30: 147-154
Methods that will be used:
We plan to determine the structure of the N-terminal domain of ClpG, which mediates the binding to protein aggregates, by X-ray crystallography or NMR spectroscopy. The structure will be validated by site-specific crosslinking experiments and designed mutants that will be characterized by a multiplicity of biochemical and cell biological methods. A combinatorial set of methods will also be used to dissect the potential interplay with other chaperones.
Cooperation partners:
Irmgard Sinning (BZH, Heidelberg), Marta Carroni (SciLifeLab, Stockholm), Ute Römling (Karolinska Institute, Stockholm)
Personal qualifications:
We seek for a person with great interest in fundamental research and an expertise in biochemistry and microbiology.
chaperone, protein structure, protein aggregates, heat resistance