About the Project
RAS proteins are central molecular switches in human signalling and are among the most frequently mutated proteins in cancer. Yet, despite decades of structural studies, we still do not fully understand how the environment in which RAS actually functions – the plasma membrane – shapes its structure, dynamics and signalling [1]. Recent work has shown that molecular environments can profoundly remodel RAS conformational ensembles; for example, the negatively charged ribosome surface encountered…
during biosynthesis can stabilise alternative, partially unfolded states [2]. This project will investigate how analogous environmental effects operate in the native functional context of RAS at the plasma membrane.
The student will compare the conformational ensembles of soluble and membrane-tethered RAS using defined membrane models, including nanodiscs with precisely controlled lipid compositions. This will establish how membrane charge and lipid chemistry reshape RAS conformational populations and provide a foundation for understanding how these changes relate to signalling output. A major focus will be the detection and structural characterisation of transient and low-population RAS conformations that are difficult to capture using conventional structure determination but may be critical for signalling. The student will use hydrogen–deuterium exchange mass spectrometry (HDX-MS) to probe RAS dynamics, working closely with the state-of-the-art mass spectrometry facilities at the LMB. These measurements will be integrated with molecular dynamics simulations and conformational ensembles generated using modern generative AI models [3] to obtain high-resolution descriptions of the RAS conformational landscape. The work will be complemented by 19F NMR, which provides an orthogonal and sensitive probe of alternative conformational states [4], together with biochemical, biophysical and cellular experiments linking structural ensembles directly to RAS function.
This project offers the opportunity to work at the interface of structural biology, biophysics, mass spectrometry and computational modelling while addressing a fundamental question in membrane signalling.
References
- Van Q.N. et al. (2020). Uncovering a membrane-distal conformation of KRAS available to recruit RAF to the plasma membrane. PNAS 117, 24258–24268. https://doi.org/10.1073/pnas.2006504117
- Streit J.O. et al. (2024). The ribosome lowers the entropic penalty of protein folding. Nature 633, 232-239. https://doi.org/10.1038/s41586-024-07784-4
- Streit J.O. et al. (in preparation). Integrating hydrogen-exchange experiments with conformational ensembles.
- Streit J.O. et al. (2025). Rational design of 19F NMR labelling sites to probe protein structure and interactions. Nat Commun 16, 4300. https://doi.org/10.1038/s41467-025-59105-6
