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Katherine Stott

The role of disordered proteins in nucleic acid condensation and scaffolding

Intrinsically-disordered proteins (IDPs) play an essential role in a wide variety of biological processes. For many years, molecular recognition of IDPs by their partners has been assumed to involve a disorder-to-order transition. However, more recently several examples of stable complexes have been characterised in which the proteins retain a high level of disorder, populating multiple functionally-relevant bound states, so-called “fuzzy complexes”. Their discovery has brought about a paradigm shift in the area of structural biology.

Many IDPs have low sequence complexity. Since many members of the eukaryotic proteome contain stretches of low-complexity sequence, their complexes are likely to be widespread. We study the recognition mechanisms and functions of IDPs in two areas in which they play a key role: DNA condensation and scaffolding. Within these areas, we are particularly interested in the functional consequences of post-translational modifications to IDPs, and IDPs as drivers of liquid de-mixing by phase separation into condensates (which can take the form of dense liquid droplets, liquid crystals or gels). Our interests extend from these curiosity-driven questions to translational possibilities; we are also engaged in a joint effort with the McNaughton group at King’s College London to block the interaction of a disordered scaffold protein (AKAP79) with the capsaicin receptor, TRPV1, in a novel take on an old analgesic target.

We use a range of biophysical methods, solution-state X-ray/neutron scattering and NMR, and make extensive use of the in-house biophysics and NMR facilities.

Read a summary of our latest work here.

Applications from prospective students are always welcomed.

Lab members: Teresa Almeida, Christina Hanack, Matthew Watson

Biophysics facility: Paul Brear, Simon Quick

Key publications:

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 USA, DOI: 10.1073/pnas.1805943115.

Stott K, Watson M, Bostock MJ, et al. (2014) Structural Insights into the Mechanism of Negative Regulation of Single-box High Mobility Group Proteins by the Acidic Tail Domain. J Biol Chem 289:29817–29826.

Btesh J, Fischer MJ, Stott K, McNaughton PA (2013) Mapping the Binding Site of TRPV1 on AKAP79: Implications for Inflammatory Hyperalgesia. J Neurosci 33:9184–9193.

Thomas JO, Stott K (2012) H1 and HMGB1: modulators of chromatin structure. Biochem Soc Trans 40:341–6.

Stott K, Watson M, Howe FS, et al. (2010) Tail-mediated collapse of HMGB1 is dynamic and occurs via differential binding of the acidic tail to the A and B domains. J Mol Biol 403:706–22.