Postdoctoral Research Scientist – Cellular Degradation Systems – London, United Kingdom

Salary for this Role:

From £38,300, subject to skills and experience.

Job Title:

Postdoctoral Research Scientist – Cellular Degradation Systems Lab

Reports to:

Anne Schreiber

Closing Date:

21/Feb/2022 23.59 GMT

Job Description:

Summary

The Schreiber lab is looking for a highly motivated enthusiastic Project Research Scientist (PRS) to study the regulation of autophagy by protein phosphatases. This will involve screening candidate phosphatases by carrying out focused CRISPR-Cas9 knockout screens and subsequent functional, biochemical and/or structural characterization. The successful candidate will have experience in mammalian cell culture and genome editing techniques and ideally an excellent knowledge of autophagy, protein phosphatases or membrane trafficking. In the first instance this is a fixed-term position, but it can be extended further depending on progress and funding.

The Research Group

The Schreiber lab is an enthusiastic curiosity-driven lab at the Francis Crick Institute (London, UK) with the aim to unravel the molecular and structural basis of autophagy to aid treatment of diseases frequently associated with deregulation of autophagy (e.g. infection, neurodegeneration and cancer) and to exploit the rejuvenescent properties of autophagy to benefit human health.

Housed in the Francis Crick institute, we benefit from access to a wealth of science technology platforms equipped with state-of-the-art infrastructure and highest-level technical expertise providing the lab with an optimal environment for carrying out cutting edge interdisciplinary research.

Project description

How does the cell form a customized waste basket when bacteria suddenly invade the cytoplasm, when mitochondria stop functioning threatening the cell by releasing reactive oxygen species or when nutrients become so scarce that the cell needs to reclaim and recycle a diverse range of cellular building blocks?

Autophagy holds the answer to all those seemingly unrelated challenges a cell may face throughout its life. Autophagy initiates a fascinating cellular response by converting small vesicles into sheet-like structures which upon closure give rise to double membrane vesicles also known as autophagosomes. Fusion with the lysosome/vacuole triggers degradation of its engulfed content allowing for the recycling and repurposing of all contained cellular building blocks. This equips the cell with a remarkable ability to adapt to its ever-changing environment by maintaining cellular homeostasis despite challenging environmental conditions. Additionally, autophagy also equips the cell with the ability to neutralize potentially cytotoxic threads such as invading pathogens, damaged organelles or protein aggregates explaining the many beneficial properties attributed to autophagy for human health. Consequently, deregulation of autophagy is associated with many human diseases such as cancer, neurodegeneration and infection.

Autophagy is a captivating but also very complex process which requires multiple cellular factors and layers of regulation. The individual steps involved are difficult to study solely in the crowded environment of the cell. Hence, the lab has developed a cell-free system to re-build the process of autophagosome formation in the test tube to understand when, where and how each of the components contributes to autophagosome formation. Such system can be manipulated at will, allowing us to dissect and visualize the different steps in order to gain unprecedented insights into the molecular mechanism.

Recent work has elucidated the regulation of autophagy by its master regulator the Atg1 kinase (Ulk1/Ulk2 in H. sapiens). Unexpectedly, we find that Atg1 mediated phosphorylation inhibits two of the key processes required for autophagy – Atg8 lipidation and Atg1 complex assembly. Therefore, temporospatial dephosphorylation of the inhibitory phosphorylation sites is required to drive autophagy. The goal of this project is to identify the corresponding protein phosphatases which regulate bulk and selective autophagy and to understand their targets, regulation, recruitment and mechanism of action employing a combination of structural, biochemical, biophysical and cellular approaches.

Key responsibilities

These include but are not limited to:

• • Identify protein phosphatases required for bulk or selective autophagy
  • Generate knockout cell lines using CRISPR-Cas9
  • Carry out cellular assays to study bulk and selective autophagy in knockout cell lines
  • Identify protein phosphatase substrates

Key experience and competencies

The post holder should embody and demonstrate our core Crick values: bold, imaginative, open, dynamic and collegial, in addition to the following:

Qualifications, experience and competencies

Essential

• PhD in a relevant field or in the final stages of PhD submission
• Extensive experience in mammalian cell culture
• Experience with gene editing techniques (CRISPR-Cas9)

Desirable

• Experience with fluorescence microscopy
• Experience with mass spectrometry-based approaches (e.g phosphoproteomics, HDX or SWATH)
• Knowledge of studying autophagy or membrane trafficking in mammalian cells

For more information please contact: anne.schreiber@crick.ac.uk.

References/Further Reading

Schreiber, A., Collins, B.C., Davis, C., Enchev, R.I., Sedra, A., D’Antuono, R., Aebersold, R., and Peter, M. (2021). Multilayered regulation of autophagy by the Atg1 kinase orchestrates spatial and temporal control of autophagosome formation. Mol Cell.

Dikic, I., and Elazar, Z. (2018). Mechanism and medical implications of mammalian autophagy. Nat Rev Mol Cell Bio 19, 349–364.

Hurley, J.H., and Young, L.N. (2016). Mechanisms of Autophagy Initiation. Annu. Rev. Biochem. 86, annurev–biochem–061516–044820.

Noda, N.N., and Inagaki, F. (2015). Mechanisms of Autophagy. Annu Rev Biophys 44, 101–122.

Schwille, P., Spatz, J., Landfester, K., Bodenschatz, E., Herminghaus, S., Sourjik, V., Erb, T., Bastiaens, P., Lipowsky, R., Hyman, A., et al. (2018). MaxSynBio ‐ Avenues towards creating cells from the bottom up. Angew. Chem. Int. Ed. Engl.