Recruitment for the position below will be done together the other positions available within the FLOW project. For the recruitment procedure and contact information, please go to the recruitment page of the FLOW website. The other available positions in the FLOW project can also be found on this website.
Current position
Decision-making on the fate of damaged proteins
Principal Investigator: Stefan Rüdiger.
Key collaborations: Mireille Claessens, Kasia Tych, Anne Wentink (project 1);
Mireille Claessens, Alfred Vertegaal, Monique Mulder, Friedrich Förster (project 2)
Main research questions
1. How do molecular chaperones control the fate of damaged proteins?
2. How do shape and properties of protein aggregates determine their fate?
Background and goals (project 1)
The aim of this project is to uncover how the central decision-making node between (re)folding and degradation works. The Hsp70-Hsp90 axis constitute the central, universally conserved a chaperone axis. Key components of this node are the conserved Hsp70 and Hsp90 chaperone systems. This axis shuttles misfolded proteins between (re)folding, reactivation and degradation. The Rüdiger group established that Hsp90 acts downstream of Hsp70, releasing an Hsp70-inflected folding block. This offers the opportunity for a plethora of co-chaperones to tweak the system. The molecular basis for the modulation of the system is poorly understood. This project aims to uncover the molecular mechanism of decision-making between reactivation and removal. We use as paradigmatic substrates a-synuclein fibrils and soluble, aggregation-prone CFTR domains. We aim to deliver a long-standing dream of the molecular life sciences, which is to understand the system to such an extent that we can rebuild the key component and to modulate the chaperone machinery at will.
Background and goals (project 2)
This project aims to determine the relation of the shape of damaged protein and the degradation channel. The Rüdiger group established the use of FIDA technology in combination with fibril paint to monitor the size of damaged protein. This now allows for the first time a quantitative, substrate driven view to determine their fate. The project will establish the influence of size, length and shape of protein aggregates in the triaging of degradation. The goal is to identify the entry criteria for degradation by the proteasome and by autophagy, and how cellular factors and drugs can influence this decision. The project centres chiefly on a-synuclein fibrils, while misfolded CFTR domains serve as comparison.
Key techniques
Protein chemistry and biophysical methods, including microscale methods such as FIDA, thermophoresis, sensitive fluorescence methods, EM and light scattering techniques.
Profile/background candidate
We are seeking candidates with background in (bio)chemistry, (bio)physics, medical biology or related fields.
Key references
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- Aragonès Pedrola J, Dekker FA, Garfagnini T, Mayer G, Koopman MB, Bergmeijer M, Förster F, Hoozemans JJM, Jensen H, Friedler A#, Rüdiger SGD#. Fibril Paint to detect Amyloids and determine Fibril Length. bioRxiv 2023; 10.13.562220. doi: https://doi.org/10.1101/2023.10.13.562220
- Koopman MB, Ferrari L, Rüdiger SGD#. How do protein aggregates escape quality control in neurodegeneration? Trends Neurosci. 2022, 45, 257-271. doi: 10.1016/j.tins.2022.01.006
- Ferrari L, Stucchi R, Konstantoulea K, van de Kamp G, Kos R, Geerts WJC, Bezouwen LS, Förster FG, Altelaar M, Hoogenraad CC, Rüdiger SGD#. Arginine pi-stacking drives binding to fibrils of the Alzheimer protein Tau. Nature Comm. 2020; 11:571. doi: 10.1038/s41467-019-13745-7
- Morán Luengo T, Mayer MP, Rüdiger SGD#. The Hsp70-Hsp90 Chaperone Cascade in Protein Folding. Trends Cell Biol. 2019. 29:164-177.
doi: 10.1016/j.tcb.2018.10.004. Epub 2018 Nov 28. PMID: 30502916. - Morán Luengo T, Kityk R, Mayer MP#, Rüdiger SGD#. Hsp90 breaks the deadlock of the Hsp70 chaperone system. Mol Cell. 2018;70:545-552. doi: 10.1016/j.molcel.2018.03.028