About the Project
Molecular chaperones are responsible for the maintenance and regulation of cellular proteins, and thus represent key targets for understanding and preventing a wide range of diseases. Chaperones may facilitate protein folding, target misfolded proteins for degradation, and/or prevent protein aggregation, either acting alone or in concert with other members of the chaperone network. The Hsp40-Hsp70 system is a key component of this network and thus is essential for cell viability. We have recently proposed that a short linker in Hsp40 provides a previously unknown layer of regulation of this vital cellular machine, while through intricate conformational changes Hsp40s alone can protect against protein aggregation – a process associated with neurodegeneration and cell death. Gaining a deeper understanding into precisely how Hsp40 regulates the chaperone network will unveil new ways in which we can modulate the chaperone network to target specific substrates and prevent related diseases.
Dynamic systems such as chaperones, require the application of sensitive biophysical tools that can visualise protein motions across various timescales. Nuclear magnetic resonance (NMR) spectroscopy is a powerful technique that is uniquely capable of studying the structure and dynamics of flexible proteins in solution at atomic resolution. In this project, you will use and develop NMR methods, in combination with mass spectrometry and atomic force microscopy, to study the equilibria that underpin Hsp40 function, as well as its interactions with Hsp70 and substrate proteins. This integrative approach applies biophysical techniques and computational analysis to understand how molecular chaperones protect the cell against protein aggregation and neurodegeneration.
The appointed student will carry the proposed research in the Astbury Centre for Structural Molecular Biology. The centre houses three modern NMR spectrometers (including a state-of-the-art 950 MHz instrument) and is well-known for its world-leading integrative structural research. You will receive extensive training in applying and developing NMR methods, molecular biology, the quantification of complex biological equilibria, and the integration of various structural techniques.
You should have at least an upper-second class or equivalent degree in Physics, Biology, Biochemistry, Biophysics, Bioengineering, or related topic. Practical experience in programming or protein expression/purification is beneficial but training in all required skills will be provided.
2. Karamanos TK, Tugarinov V, & Clore GM (2020) An S/T motif controls reversible oligomerization of the Hsp40 chaperone DNAJB6b through subtle reorganization of a β sheet backbone. Proc. Natl. Acad. Sci. USA:202020306.
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