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Shedding new light on single protein-lipid membrane interactions


   Cardiff School of Biosciences


About the Project

The interaction between proteins and lipid membranes is a fundamental process underpinning key functions in cell biology and the maintenance of life. Membrane proteins account for approximately 27% of the entire human proteome, and membrane receptors make up the largest group of drug targets in humans since they play a critical role in both infection and immunity [1]. Membranes are also the target for protein toxins produced by pathogens to attack cells from the outside and introduce perforations. Beyond their impact to human disease, toxins are of great interest in biotechnology, to control e.g. insect pests of agriculture [2]. Moreover, the challenge of antimicrobial resistance has ignited strong interest in antimicrobial peptides (AMPs) which form membrane-spanning pores as part of their bactericidal activity [3].

Despite the widespread importance of such systems, many key questions are still unanswered, including how do proteins remodel and diffuse within membranes in space and time? Where do they partition, depending on the heterogeneous lipid membrane chemical composition and curvature? How is the protein function modulated by the lipid environment at the atomic, molecular and long-range meso-scale? How is the lipid membrane local composition and curvature affected by the protein (an interplay often overlooked).

A major roadblock in achieving this understanding is the lack of suitable techniques capable of measuring single protein-lipid membrane interactions at the nanoscale with sub-millisecond time resolution, while keeping the system under observation in its intact natural state and without introducing structural-functional artefacts. Optical microscopy is a promising non-destructive and non-contact technique. However, to achieve the required sensitivity and specificity, presently it relies on tagging proteins and/or lipids, typically with fluorophores, which raises the question if the observed behaviour is real or artefactual [4].

The aim of this project is to contribute to the development and application of novel label-free optical imaging techniques to quantify the diffusion and partitioning of single proteins in physiologically relevant lipid membranes.

Research Environment: You will be exposed to a vibrant multi-disciplinary environment at the physics/life science interface. You will join a well-funded academic team, with an outstanding track record of student supervision and publication output. The supervisory team offers a unique combination of expertise, with strong track records in developing novel optical microscopy techniques applied to bioimaging (see e.g [5,6]). You will be immersed in a collaborative environment with expertise in the biology of pore forming proteins and in the biochemistry of lipid membranes. 

Training and Development Opportunities: You will be trained in a variety of relevant techniques including optical microscopy, fabrication of synthetic lipid membranes, protein purification. You will develop the transferable skills of data analysis and modelling, communication and dissemination. The resulting skillset will boost your future employability both in academia and in industry. The supervisory team has strong links with companies, including microscope manufactures and image analysis software developers. Within this studentship, opportunities for visits/internships at these companies will arise. Global mobility opportunities will include visiting collaborating partner groups overseas, and participation to national/international conferences. The project will generate new knowledge and data that will be published in high quality journals. 

It is ideal that an applicant has an A-level in maths and physics (or equivalent).


References

[1] https://doi.org/10.1038/nrd3478
[2] https://doi.org/10.3390/toxins6123296
[3] https://doi.org/10.3389/fcimb.2016.00194
[4] http://dx.doi.org/10.1038/nphoton.2015.251
[5] http://dx.doi.org/10.1021/acs.analchem.0c03179
[6] http://dx.doi.org/10.1063/1.5027256

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