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Imaging viruses and cells by electron cryomicroscopy (cryoEM)

  • Full or part time
    Dr P Rosenthal
  • Application Deadline
    Tuesday, November 12, 2019
  • Funded PhD Project (Students Worldwide)
    Funded PhD Project (Students Worldwide)

Project Description

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

Our group studies the architecture of large protein assemblies in order to understand basic molecular mechanisms that control protein and membrane traffic in the cell and in virus infection. Recently, the technique of electron cryomicroscopy (cryoEM) has made revolutionary advances in its ability to image biological specimens at high resolution. We apply cryoEM, in association with other physical techniques, to study structural problems associated with lipid enveloped viruses, molecular machines, and organelle and cellular architecture, using either single particle analysis or cryotomography.

The lipid-enveloped influenza virus is a major human pathogen. We are interested in understanding how influenza virus enters the cell by binding to cell surface receptors, how the virus membrane fuses with host membranes, and how the virus assembles and releases from the cell. We have previously performed high-resolution studies of influenza virus ultrastructure by cryotomography that have shown us the internal architecture of the virus as well as the structure of envelope glycoproteins in situ. We have also visualised snapshots of influenza virus fusing with membranes. Influenza virus membrane fusion is mediated by conformational changes in the hemagglutinin (HA) that occur at the low pH of the endosome. A major focus of this student project is to understand how changes in HA structure are coupled to transformations in membranes.

In our studies of cell architecture, we are interested in the endothelial cells that line the inner surfaces of blood vessels which play roles in hemostasis, thrombosis, and inflammation by secretion of the large, multimeric blood glycoprotein von Willebrand factor (VWF). VWF has multiple ligands and on acute release, functions as an adhesive protein to bind platelets to sites of vascular injury. Defects in VWF and its storage are responsible for bleeding disorders including von Willebrand’s disease. VWF is stored for rapid exocytic release in specialized secretory organelles called Weibel-Palade bodies (WPBs). Our studies are focused on understanding how VWF is organized for dense storage in WPBs, and in a structural and physical understanding of how VWF is released when granules fuse with the plasma membrane during exocytosis.

We also work to improve experimental imaging and develop new computational methods for image analysis. While a single studentship is available, other topics for study will be considered in consultation with the advisor. The student will receive training in experimental cryomicroscopy, computational image analysis, protein, membrane and virus methods, biophysical methods, and imaging of cells by light microscopy.

Candidate background
This multidisciplinary project will interest students in structural biology, virology and/or cell biology. The ideal candidate will have experience of experimental methods in biology and a strong background and interest in physical or computational sciences. However, a wide range of applicants in the biological or physical sciences will be considered.


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 2020 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) 13 NOVEMBER 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. Benton, D. J., Nans, A., Calder, L. J., Turner, J., Neu, U., Lin, Y. P., . . . Skehel, J. J. (2018)

Influenza hemagglutinin membrane anchor.

Proceedings of the National Academy of Sciences of the United States of America 115: 10112-10117. PubMed abstract

2. Calder, L. J. and Rosenthal, P. B. (2016)

Cryomicroscopy provides structural snapshots of influenza virus membrane fusion.

Nature Structural & Molecular Biology 23: 853-858. PubMed abstract

3. Calder, L. J., Wasilewski, S., Berriman, J. A. and Rosenthal, P. B. (2010)

Structural organization of a filamentous influenza A virus.

Proceedings of the National Academy of Sciences of the United States of America 107: 10685-10690. PubMed abstract

4. Streetley, J., Fonseca, A.-V., Turner, J., Kiskin, N. I., Knipe, L., Rosenthal, P. B. and Carter, T. (2019)

Stimulated release of intraluminal vesicles from Weibel-Palade bodies.

Blood 113: 2707-2717. PubMed abstract



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