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Organisational and regulatory roles of disordered proteins


Department of Biochemistry

Applications accepted all year round Awaiting Funding Decision/Possible External Funding

About the Project

Proteins are often depicted as visually compelling three-dimensional arrangements of alpha helices and beta sheets that recognise their biological partners via structurally complementary surfaces, like the pieces of a jigsaw puzzle. However, a sizeable fraction of proteins are intrinsically disordered, or contain intrinsically-disordered regions, and it is increasingly appreciated that disordered proteins play an essential role in a wide variety of biological processes.

Our research is focused on two areas in which disordered proteins are key players in the organisation and regulation of a molecular assembly: (i) gene expression via chromatin (de)condensation, and (ii) signalling via protein-protein interaction hubs. Our aim in each case is to gain an atomic-level understanding of representative complexes that will inform on a general mechanism, focusing on what is usually the least understood part; the disordered protein. We use a broad methodology, including a range of biophysical methods, solution-state X-ray/neutron scattering and NMR, making extensive use of the Department’s in-house biophysics and NMR facilities, with all the training opportunities they bring. Our recent findings include the development of a chromatin model, with which we established the role of ’fuzzy complexes’ and liquid-liquid phase separation in the condensation of DNA by linker histone tails, and its regulation by phosphorylation. The model is a compelling view of chromatin that accounts for its ability to respond to external stimuli, e.g. reversibly up- and down-regulating overall levels of gene expression during the cell cycle.

The skills in the lab range from cell and molecular biology through to structural biology and biophysics. Therefore, the precise nature of the PhD project can be adjusted to some extent according to the interest and expertise of the applicant.

Applications should be sent to Katherine Stott (), including a CV detailing academic achievements so far, a motivational statement and the names and contact details of two referees.

Funding Notes

Funding can be obtained via Cambridge MRC or BBSRC DTPs, through Departmental AstraZeneca Studentships or via various Cambridge Scholarships including those for overseas students.

References

Watson M, Stott K (2019). Disordered domains in chromatin-binding proteins. Essays Biochem., 63(1):147-156. doi: 10.1042/EBC20180068

Turner AL, Watson M, Wilkins OG, Cato L, Travers A, Thomas JO, Stott K (2018). Highly disordered histone H1-DNA model complexes and their condensates. Proc. Natl. Acad. Sci. U.S.A., 115(47):11964-11969. doi: 10.1073/pnas.1805943115

Stott K, Watson M, Bostock MJ, Mortensen SA, Travers A, Grasser KD, Thomas JO (2014). Structural insights into the mechanism of negative regulation of single-box high mobility group proteins by the acidic tail domain. J. Biol. Chem., 289(43):29817-29826. doi: 10.1074/jbc.M114.591115

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