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Understanding the structural and mechanistic basis of autophagy

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  • Full or part time
    Dr A Schreiber
  • Application Deadline
    No more applications being accepted
  • Funded PhD Project (Students Worldwide)
    Funded PhD Project (Students Worldwide)

Project Description

This 4-year PhD studentship is offered in Dr Anne Schreiber’s Group based at the Francis Crick Institute (the Crick).

Cells have evolved different means to degrade their cellular constituents. While the ubiquitin proteasome system selectively degrades proteins marked by ubiquitin, autophagy can target a variety of different cellular components simultaneously by growing a double membrane vesicle around them and delivering the engulfed content for degradation in the lysosome/vacuole. This not only allows for the recycling of virtually all cellular building blocks but also provides the cell with a universal means to neutralize potentially harmful cytoplasmic threads such as damaged organelles (e.g. mitochondria or peroxisomes), protein aggregates or invading intracellular pathogens (e.g. bacteria and viruses). Intriguingly, autophagosome formation happens in a fully de novo fashion and can be triggered by a diverse range of stimuli making autophagy not only a fascinating subject from a mechanistic but also from a regulatory and signalling point of view.

Modulating autophagy holds great promise for treating cancer, neurodegenerative and infectious diseases and slowing down ageing. However, its fundamental importance is cast in sharp contrast to our very limited understanding of its molecular and structural underpinnings.

In order to overcome the technical limitations of studying the molecular mechanism of autophagosome formation in vivo, the lab has established an in vitro reconstitution approach allowing us to study the complex interplay of the autophagy machinery and their regulation in unprecedented mechanistic detail. We utilize the system to uncover how the autophagy machinery drives autophagosomal membrane formation working towards our overarching goal of reconstituting autophagosome formation in the test tube and visualising the functional states by cryo-electron microscopy techniques.

In this PhD project, we aim to understand the structural and mechanistic basis of autophagosome formation by using a combination of structural, biochemical and biophysical approaches. We will take advantage of recent advances in cryo-electron microscopy to visualise high resolution snapshots of the autophagy machinery at work. We are also interested in the cargo recognition stages and the signalling events underlying selective autophagy pathways such as the elimination of damaged mitochondria (mitophagy). Ultimately, we will use model organism such as budding yeast to validate our findings in vivo.

There is only one studentship available within the group, however, within the wider structural and mechanistic framework of the proposed project the final PhD project can be tailored depending on the candidate’s background and interests.

Most of the protocols and reagents are already available. Producing the proteins, multi-subunit complexes and transmembrane proteins involved will nevertheless be a central aspect of the project. The successful candidate will also benefit from all the enzymatic assays set up in the lab to study the functionality and regulation of the autophagy machinery and the tools to study autophagy in vivo. The Francis Crick Institute provides a cutting edge infrastructure allowing training and access to state of the art technology and expertise enabling a unique experimental approach.

Candidates should have a strong interest in cryo-EM, biochemistry, membrane biology or biophysics but even more importantly candidates should have a natural curiosity and enjoy the process of discovery.

Talented and motivated students passionate about doing research are invited to apply for this PhD position. The successful applicant will join the Crick PhD Programme in September 2019 and will register for their PhD at one of the Crick partner universities (Imperial College London, King’s College London or UCL).

Applicants should hold or expect to gain a first/upper second-class honours degree or equivalent in a relevant subject and have appropriate research experience as part of, or outside of, a university degree course and/or a Masters degree in a relevant subject.

APPLICATIONS MUST BE MADE ONLINE VIA OUR WEBSITE (ACCESSIBLE VIA THE ‘APPLY NOW’ LINK ABOVE) BY 12:00 (NOON) MARCH 19 2019. APPLICATIONS WILL NOT BE ACCEPTED IN ANY OTHER FORMAT.

Funding Notes

Successful applicants will be awarded a non-taxable annual stipend of £22,000 plus payment of university tuition fees. Students of all nationalities are eligible to apply.

References

1. Hurley, J. H. and Nogales, E. (2016)
Next-generation electron microscopy in autophagy research.
Current Opinion in Structural Biology 41: 211-216. PubMed abstract
2. Hurley, J. H. and Young, L. N. (2017)
Mechanisms of autophagy initiation.
Annual Review of Biochemistry 86: 225-244. PubMed abstract
3. Noda, N. N. and Inagaki, F. (2015)
Mechanisms of autophagy.
Annual Review of Biophysics 44: 101-122. PubMed abstract
4. Rao, Y., Perna, M. G., Hofmann, B., Beier, V. and Wollert, T. (2016)
The Atg1-kinase complex tethers Atg9-vesicles to initiate autophagy.
Nature Communications 7: 10338. PubMed abstract
5. Schwille, P., Spatz, J., Landfester, K., Bodenschatz, E., Herminghaus, S., Sourjik, V., . . . Sundmacher, K. (2018)
MaxSynBio - Avenues towards creating cells from the bottom up.
Angewandte Chemie International Edition: Epub ahead of print. PubMed abstract



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