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Archiv-Übersicht     Angebot Nr. 13083

Angebotsdatum: 16. Oktober 2018
Art der Stelle: Doktorarbeit
Fachgebiet: Biologie > Molekularbiologie
Titel des Themas: Mechanism of stand-alone disaggregase conferring superior heat resistance

Institut: Zentrum für Molekulare Biologie der Universität Heidelberg
PD Axel Mogk
Im Neuenheimer Feld 282
69120 Heidelberg
Tel.: 06221 546863   Fax.:
Bundesland: Baden-Württemberg
Homepage: http://https://www.zmbh.uni-heidelberg.de/bukau/default.shtml
E-Mail Kontakt: mail

Beschreibung: Summary:
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 solubilize protein aggregates by an ATP-driven threading activity. Classical AAA+ disaggregases require cooperation with partner chaperones for targeting to protein aggregates and stimulation of ATPase activity. We recently identified a novel AAA+ disaggregase, ClpG, which does not require partner assistance. ClpG functions as stand-alone and highly efficient disaggregase and confers superior heat resistance to bacteria. Thereby ClpG promotes bacterial survival during temperature-based sterilization methods used in modern food production and medical sterilization procedures and contributes to persistence in e.g. the hospital environment.
The project aims at the mechanistic understanding of ClpG disaggregation activity. How does ClpG specifically recognize protein aggregates? How is aggregate binding coupled to activation of ATPase and threading activities? Can ClpG also provide superior heat resistance to eukaryotic cells? The study will provide important insights into disaggregase function and can provide basis for rationale drug design.

We offer:
The PhD student will be part of the Bukau lab (https://www.zmbh.uni-heidelberg.de/bukau/default.shtml), which belongs to the top groups in chaperone research. The lab offers a stimulatory atmosphere, great expertise and a vast variety of methods. Intense training and guidance will be provided by a senior scientist. Preliminary work on the project allows for fast start and a completion of the thesis within three years.
The PhD student will be enrolled in the “Heidelberg Biosciences International Graduate School (HBIGS)”.
Methoden: Determine ClpG structure by X-ray crystallography and/or NMR spectroscopy. Validate the structure by e.g. site-specific crosslinking experiments and designed mutants that will be characterized by a multiplicity of biochemical and cell biological methods. Conformational dynamcis of ClpG will be monitored by H/D exchange experiments coupled to mass spectrometry.
Anfangsdatum: 16. Oktober 2018
Geschätzte Dauer: 3 Jahre
Bezahlung: PhD position, 65%, 3 years
Papers: 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

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

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