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(BBSRC NWD) Establishing a nanodisc system to probe integrin regulation using Nuclear Magnetic Resonance (NMR) and Cryogenic Electron Microscopy (Cryo-EM)

Funding
Funded
Study mode
Full-time
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Start date
Subject area
Biological and Biomedical Sciences
How to apply
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Overview

Cells in multicellular organisms connect to the extracellular matrix through integrin adhesion receptors. These receptors not only provide physical attachment to surfaces, but also act as communication gateways, enabling cells to respond to changes in their environment. When this communication breaks down, cells can no longer grow, migrate, or maintain and repair tissues, resulting in diseases such as cancer, fibrosis, and impaired wound healing.

About this opportunity

Integrins exist in inactive and active states, and only the active form mediates cell adhesion. Their activity is controlled by proteins that bind to a small intracellular region of the receptor. The best-studied of these regulators are the adaptor proteins talin and kindlin. Both are required for integrin activation and for the formation of adhesion structures. A third, much less studied regulator is tensin, which is essential for the development of stable adhesions that maintain tissue integrity. A major unanswered question is how these regulatory proteins work together on the membrane, as no structures of the fully assembled, membrane-bound activation complexes are currently available.

The aim of this project is to understand how the interplay of the three adapter proteins, talin, kindlin and talin, control integrin activity. We will achieve this by reconstructing fully functional integrin complexes in a native-like membrane environment (nanodiscs) and determining their activation state and molecular structure. The gained structural insights will then guide experiments in living cells to investigate integrin regulation under physiological conditions.

As the successful candidate, you will work in a highly collaborative, interdisciplinary environment, alongside research groups in Liverpool and Manchester. These groups have extensive experience in cell adhesion research and have collaborated in the past. The first stage of the project involves establishing the nanodisc platform with embedded integrins to enable the controlled assembly of integrin regulatory complexes with adapter proteins. You will then use NMR spectroscopy in combination with spin labelling and high-resolution cryo-EM to determine the molecular structures and dynamics of the integrin complexes. This structural analysis will be supported by advanced modelling approaches, including machine learning tools such as AlphaFold, as well as molecular dynamics simulations. Using the structural data, you will then design mutations to alter specific regulatory protein-protein interactions. These mutations will be introduced into cells via gene editing and the resulting adhesion processes will be studied using high-resolution fluorescence microscopy.

This multidisciplinary project provides hands-on training in:

  • Protein engineering, purification and nanodisc reconstitution (Barsukov lab, Liverpool)
  • Advanced biophysical and structural techniques including high-resolution NMR, isotope/spin labelling, ITC and BLI (Barsukov lab, Liverpool)
  • X-ray crystallography and cryo-EM (Zacharchenko lab, Manchester)
  • Mammalian cell culture, genetic manipulation, high-resolution fluorescence microscopy and functional cell assays (Ballestrem lab, Manchester)

Overall, this PhD is a unique opportunity to use cutting-edge methods in structural and cell biology, which could lead to new ways to treat diseases by targeting how cells communicate.

Further reading

1. Elliott, P.R., et al., The Structure of the Talin Head Reveals a Novel Extended Conformation of the FERM Domain. Structure, 2010. 18(10): p. 1289-1299.
2. Atherton, P., et al., Tensin3 interaction with talin drives the formation of fibronectin-associated fibrillar adhesions. J Cell Biol, 2022. 221(10): p. e202107022.
3. Li, X et al. Multidomain talin-tensin3 interactions and their role in mechanosensitive tensin3 phase separation. J Cell Biol (in press)

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Who is this for?

Eligibility

Applicants must have obtained or be about to obtain a minimum Upper Second class UK honours degree, or the equivalent qualifications gained outside the UK, in an appropriate area of science, engineering or technology.

International applicants

We are only able to offer a limited number of full studentships to applicants outside the UK. Therefore, full studentships will only be awarded to exceptional quality international candidates due to the competitive nature of this scheme.

International applicants must ensure they meet the academic eligibility criteria (including English language) before applying. Visit our English Language requirements page to find out more.

Equality, Diversity and Inclusion

Equality, diversity and inclusion is fundamental to the success of The University of Liverpool, and is at the heart of all of our activities. The full equality, diversity and inclusion statement can be found on our website.

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How to apply

  1. 1. Contact supervisors

    For informal enquiries, please contact: Dr Igor Barsukov ()

    Supervisors:

  2. 2. Prepare your application documents

    Browse our BBSRC NWD in Bioscience projects and discover one you’re passionate about that matches your interests, ambitions and goals.

    Applicants must make direct contact with preferred supervisors before applying. It is your responsibility to make arrangements to meet with potential supervisors, prior to submitting a formal online application.

    How to Apply

    All applications should be submitted through the University of Manchester application portal.

    Apply directly via this link, and select BBSRC DTP PhD as the programme of study. You may apply for up to two projects from the programme via this scheme. To do so, submit a single online application listing both project titles and the names of both main supervisors in the relevant sections.

    Please ensure that your application includes all required supporting documents:

    • Curriculum Vitae (CV)
    • Supporting Statement
    • Academic Certificates and Transcripts

    Incomplete or late applications will not be considered.

    Applications should not be made through the University of Liverpool’s application portal.

    You must submit your application form along with the required supporting documents by the deadline date. You can select up to two projects on one single application, noting the title of each project from the advert and the supervisor name. This can include two projects from one institution or a project from each institution.

    Once you have completed your application, you’ll receive a confirmation email.

    Deadline: Sunday 7th December, midnight (UK time)

    Late or incomplete applications will not be considered.

    If you need help with this stage of the process, or have any queries regarding your eligibility (such as if you achieved unexpectedly low degree results due to extenuating circumstances), please contact the Liverpool BBSRC team for advice at 

  3. 3. Apply

    Finally, register and apply online. You'll receive an email acknowledgment once you've submitted your application. We'll be in touch with further details about what happens next.

    Once you have applied through the University of Manchester portal, and if you are successfully offered a studentship following a formal interview, you will be instructed to apply formally through the University of Liverpool. You must only do this once you have been instructed to do so.

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Funding your PhD

These studentships are available to UK and international applicants, and provide funding for tuition fees and stipend at the UKRI rate, subject to eligibility, for four years. This does not include any costs associated with relocation. This scheme is open to both UK and international applicants.

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Contact us

Have a question about this research opportunity or studying a PhD with us? Please get in touch with us, using the contact details below, and we’ll be happy to assist you.

Liverpool BBSRC team
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