Ruprecht-Karls-Universit├Ąt Heidelberg
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Bukau0118 - Scientist (f/m) / PhD position
Project no:
Bukau0118

Project leader:

Project supervisor:
Bukau, Bernd
Application deadline:
31. Jul 2018
Start of PhD project:
1. Sep 2018

Project description:

Title:
Mechanisms and functions of sequestrases in protein quality control networks
Summary:
The cellular proteome is constantly endangered by perturbations leading to protein unfolding and, consequently, to disease states including cancer and aging. In response, cells induce a multifaceted quality control machinery promoting repair and degradation of misfolded proteins. Only recently it became clear that an important third pillar of protein quality control is the sequestration of misfolded proteins into organized inclusions. We have identified cellular sequestrases, which promote the aggregation of misfolded proteins during stress conditions (1-4). Sequestrases include small heat shock proteins (sHsps), which organize protein aggregates for efficient targeting to chaperone-mediated refolding or autophagic pathways.

References:
1 Specht, S., Miller, S. B., Mogk, A. & Bukau, B. Hsp42 is required for sequestration of protein aggregates into deposition sites in Saccharomyces cerevisiae. J Cell Biol 195, 617-629, doi:jcb.201106037 [pii] 10.1083/jcb.201106037 (2011).

2 Miller, S. B. et al. Compartment-specific aggregases direct distinct nuclear and cytoplasmic aggregate deposition. EMBO J 34, 778-797, doi:10.15252/embj.201489524 (2015).

3 Miller, S. B., Mogk, A. & Bukau, B. Spatially Organized Aggregation of Misfolded Proteins as Cellular Stress Defense Strategy. J Mol Biol 427, 1564-1574, doi:10.1016/j.jmb.2015.02.006 (2015).

4 Ungelenk, S. et al. Small heat shock proteins sequester misfolding proteins in near-native conformation for cellular protection and efficient refolding. Nature communications 7, 13673, doi:10.1038/ncomms13673 (2016).
Methods that will be used:
This project aims to gain insights into the mechanisms and physiological importance of organized protein sequestration. Using a combination of protein biochemistry, cell biology and molecular biology and diverse model organisms it will explore (i) the mechanism by which sHsps sequester misfolded proteins, (ii) how sHsps influence subsequent triage decisions on the fate of sequestered substrates, and (iii) the physiological functions of sHsps during stress and cellular aging.
Cooperation partners:
Personal qualifications:
We are seeking for a highly motivated person that enjoys working in a team and has knowledge in molecular biology and biochemistry. The successful candidate should have interest in studying fundamental principles governing cellular protein homeostasis.
Keywords:
Protein aggregation, chaperones, protein quality control