Structural Proteomics to spatially resolve interactions with mechanosensitive synaptic scaffold proteins
- Funding
- Self-funded
- Study mode
- Full-time
- Part-time
- Apply by
- Year round
- Start date
- Year round
- Subject area
- Biological and Biomedical Sciences
Over the past decades, tremendous progress has been made in unveiling how synaptic plasticity wires and rewires neural circuits, forming the basis of learning and memory. Yet, we lack sufficient understanding of the underlying mechanisms through which molecules compute and store information in synapses. The project will combine state-of-the art technologies in a unique way to map the talin interactome during cell signalling and LTP. The supervisory team are world leading experts in the structural mechanobiology of talin, proteomics and cell adhesion biology and cell culture.
Over the past decades, tremendous progress has been made in unveiling how synaptic plasticity wires and rewires neural circuits, forming the basis of learning and memory. Yet, we lack sufficient understanding of the underlying mechanisms through which molecules compute and store information in synapses. Non-neuronal cells form focal adhesions (FAs), transmitting mechanical force through the actin cytoskeleton to the extracellular matrix (ECM). In FAs, proteins such as talin alter their structure in response to these forces, thereby rewiring the activity of intracellular signalling pathways. We hypothesize that mechanosensing is the key missing link mediating signalling in synapses, thereby encoding ‘mechano-memories.’ We propose that these are built on talin’s ability to undergo an elaborate sequence of structural transitions, which form the nexus for biochemical computations that regulate synaptic plasticity and strength.
This project is based on our exciting preliminary data of the essential role of talin in synaptic functions; i) talin contains 13 force-dependent binary switch domains that cells can open using their motor proteins, ii) talin is under tension in synapses, iii) CRISPR deletion of talin from neurons prevents long-term potentiation (LTP) and iv) mutations in the talin gene are a previously unrecognized cause of childhood epilepsy (collaboration with Boston Children’s Hospital). Our research has shown that key to talin’s capacity to orchestrate enzymatic processes is its ability to change its dimensions by >10-fold as its switch domains unfold. As a result, the enzymes decorating talin can get spatially resolved over the entire length of the synapse from 60 nm when at rest to greater than 500 nm. This leads to our central hypothesis that the talin interactome changes during LTP.
Crosslinking mass spectrometry is a powerful technology for identifying protein-protein interactions in highly complex samples. This technique employs small, reactive reagents to form covalent bonds between amino acids that are in close proximity within the protein’s native state. Following reduction, alkylation, and digestion, the resulting crosslinked peptides—two peptides bound together by the crosslinking reagent—are analysed by mass spectrometry to reveal peptide identities and the specific location of the crosslink. This process provides not only interaction details but also valuable structural information, allowing precise mapping of interaction interfaces between proteins – precisely the information relevant for this project.
The project will combine state-of-the art technologies in a unique way to map the talin interactome during cell signalling and LTP. The supervisory team are world leading experts in the structural mechanobiology of talin, proteomics and cell adhesion biology and cell culture. Our neuroscience collaborators in Finland, have provided us with neuronal cell extracts taken at different stages of LTP.
The student will be embedded in the Biochemistry, Cell and Systems Biology department at the University of Liverpool, where they will train in protein expression and purification, biochemistry and proteomics-based approaches. This interdisciplinary approach will provide them with an excellent well rounded scientific training. The supervisory team have an excellent track record of PhD student success, both in them graduating in 4 years but also in publishing papers and going on to future careers.
We will 1) optimize the structural proteomics assay with talin fragments and interactions in vitro first where the positions of binding sites are known. 2) Once the structural proteomics-based approaches are optimised for working on talin, the student will use them to map the talin interactome at sub-nanometre resolution in cell culture. Finally, the methodology will be applied in neuronal cells, to identify precisely i) what ligands are bound to talin and ii) where on talin each ligand is bound, during synaptic function and during LTP.
This project is open to UK and international applicants with their own funding. Funding should cover course fees, living expenses and research expenses (bench fees).
Please email your CV and cover letter to the primary supervisor, Prof Ben Goult, in the first instance: b.t.goult@liverpool.ac.uk
Supervisors:
| Prof Ben Goult | b.t.goult@liverpool.ac.uk | https://www.liverpool.ac.uk/people/ben-goult |
| Prof Richard Scheltema | Richard.Scheltema@liverpool.ac.uk | https://www.liverpool.ac.uk/people/richard-scheltema |
| Dr Paul Atherton | Paul.Atherton@liverpool.ac.uk | https://www.liverpool.ac.uk/people/paul-atherton |
| Prof Martin Humphries | Martin.Humphries@manchester.ac.uk | https://research.manchester.ac.uk/en/persons/martin.humphries |
You may need the following documents to complete your online application:
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.
Your tuition fees, funding your studies, and other costs to consider.
Full-time place, per year - £5,006
Part-time place, per year - £2,503
Full-time place, per year - £31,249
Part-time place, per year - £15,650
Fees stated are for academic year 2025/26 and may be subject to change for academic year 2026/27. The University may administer inflationary rises to international fees in subsequent academic years as you progress through the course.
We understand that budgeting for your time at university is important, and we want to make sure you understand any costs that are not covered by your tuition fee. This could include buying a laptop, books, or stationery.
Find out more about the additional study costs that may apply to this project, as well as general student living costs.
If you're a UK national, or have settled status in the UK, you may be eligible to apply for a Postgraduate Doctoral Loan worth up to £30,301 to help with course fees and living costs.
There’s also a variety of alternative sources of funding. These include funded research opportunities and financial support from UK research councils, charities and trusts. Your supervisor may be able to help you secure funding.
We've set the country or region your qualifications are from as United Kingdom.
We offer a range of scholarships and bursaries that could help pay your tuition fees and living expenses.
If you’re awarded this prestigious scholarship, you’ll receive significant funding to support your postgraduate research. This includes full payment of your PhD fees and a cash bursary of £23,000 per year while you study. One award is available in each academic year.
If you’re a UK student, either born in or with strong family connections to Merseyside, you could be eligible to apply for financial support worth up to £12,000 per year for up to three years of full-time postgraduate research (or up to five years part-time pro-rata).
Apply to receive tailored training support to enhance your sporting performance. Our athlete support package includes a range of benefits, from bespoke strength and conditioning training to physiotherapy sessions and one-to-one nutritional advice.
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.