Sub-cellular organisation via liquid-liquid phase separation
A central organising principle of eukaryotic cells is the compartmentalisation of biochemical reactions by membrane boundaries into organelles. However, not all processes are organised in this fashion. Cells also contain a variety of organelles and compartments such as nucleoli, Cajal bodies, P-granules and nuage that lack a membrane boundary. Often spherical in appearance and readily observable with a light microscope, these membraneless organelles are highly dynamic, and can rapidly assemble and dissolve with changes to the cellular environment. Membraneless organelles are predominantly associated with DNA and RNA processing, and have been linked with neurodegenerative diseases and viral infection. Remarkably, these organelles and compartments typically display the properties of liquid droplets, and form by the condensation of material in the cell, in a similar way to how water condenses to form rain drops.
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The liquid droplet-like nature of membraneless organelles makes them particularly challenging to work with and study, but at the same time provides many opportunities for exciting new discoveries. Our research on model membraneless organelles made of intrinsically disordered regions (IDRs) of proteins shows that the organelle interior is a unique solvent environment, with surprising emergent biochemical properties. For example, model membraneless organelles can selectively absorb and traffic proteins and structured RNAs, and melt nucleic acid duplexes without the input of ATP, essentially acting as passive helicases.
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Our major aims are to explain how the liquid properties of membraneless organelles provide a general organising principle in cells, and to understand why cells perform certain reactions inside them. To tackle these fundamental biological questions, we take a creative and interdisciplinary approach, using tools and techniques from cell biology, structural biology, polymer theory and bioinformatics. Our research is supported by the world-class Micron Advanced Bioimaging Unit and the superb suite of biophysical instruments within the Department of Biochemistry.
Find out more about our work on the Oxford Science Blog, or contact us directly.
Selected publications
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Holland J., Crabtree M.D., Nott T.J. 2020. In Vitro Transition Temperature Measurement of Phase-Separating Proteins by Microscopy. In: Kragelund B., Skriver K. (eds) Intrinsically Disordered Proteins. Methods in Molecular Biology, vol 2141. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-0524-0_36. (link)
Get transition temperature script (link to file). Replace .txt with .py |
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Brady, J.P., Farber, P.J., Sekhar, A., Lin, Y.H., Huang, R., Bah, A., Nott, T.J., Chan, H.S., Baldwin, A.J., Forman-Kay, J.D. and Kay, L.E., 2017. Structural and hydrodynamic properties of an intrinsically disordered region of a germ cell-specific protein on phase separation. Proceedings of the National Academy of Sciences, p.201706197. (link) |
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Nott, T.J., Craggs, T.D. and Baldwin, A.J., 2016. Membraneless organelles can melt nucleic acid duplexes and act as biomolecular filters. Nature Chemistry, 8(6), pp.569-575. (link) (pdf)
News and Views, Nature Chemistry (link) Editors choice, Science (link) F1000 recommended (link) Oxford Science Blog (link) |
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Nott, T.J., Petsalaki, E., Farber, P., Jervis, D., Fussner, E., Plochowietz, A., Craggs, T.D., Bazett-Jones, D.P., Pawson, T., Forman-Kay, J.D. and Baldwin, A.J., 2015. Phase transition of a disordered nuage protein generates environmentally responsive membraneless organelles. Molecular Cell, 57(5), pp.936-947. (link) (pdf) F1000 recommended (link) |
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Chen, C., Nott, T.J., Jin, J. and Pawson, T., 2011. Deciphering arginine methylation: Tudor tells the tale. Nature Reviews Molecular Cell Biology, 12(10), pp.629-642. (link) |
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Nott, T.J., Kelly, G., Stach, L., Li, J., Westcott, S., Patel, D., Hunt, D.M., Howell, S., Buxton, R.S., O’Hare, H.M. and Smerdon, S.J., 2009. An intramolecular switch regulates phosphoindependent FHA domain interactions in Mycobacterium tuberculosis. Science Signaling, 2(63), pp.ra12. (link) |
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