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Professor Jane Clarke FMedSci

Portrait of jc162

Biophysical and structural studies of protein folding

The physics and chemistry of weak molecular interactions underpin the whole of biology. These determine the structure and stability of biological macromolecules and the strength and lifetime of interactions of these macromolecules with other cellular components. Understanding how a protein folds into a specific structure (which is only marginally stable) on a biologically relevant timescale, is still a significant challenge. Fundamental biophysical studies of the folding of proteins and of protein-protein interactions are key to understanding cellular function.

We have two fundamental research areas:

(1) How do proteins fold at the atomistic level and how is misfolding avoided?
(2) How do changes in sequence, as the result of evolution, or brought about by mutation affect
the biophysical properties of proteins?


We study families of proteins using a multidisciplinary approach, to address specific questions:

  • The folding of related proteins: By comparing the folding of a number of related proteins from large structural families we can investigate the relationship between amino acid sequence and topology and protein stability.
  • The folding of multidomain proteins: Most proteins consist of a number of independently folding domains. How do domain:domain interactions modulate the properties of the protein? Importantly, how do larger, multidomain proteins avoid misfolding?

  • Intrinsically disordered proteins (IDPs): A significant proportion of proteins have large disordered segments. These proteins are often involved in important important signalling pathways. IDPs fold upon binding to a target. We are developing the tools used to study globular protein folding to investigate the mechanisms of folding of IDPs.

Selected Publications

Borgia, M. B., Nickson, A.A., Clarke J. & Hounslow, M.J. (2013) A mechanistic model for amorphous protein aggregation of immunoglobulin-like domains. J. Am. Chem. Soc., in press DOI: 10.1021/ja308852b

Rogers, J.M. Steward, A. & Clarke, J. Folding and binding of an intrinsically disordered protein: fast, but not ‘diffusion-limited’. J. Am. Chem. Soc., 135, 1415−1422 DOI: 10.1021/ja309527h

Nickson, A. A., Wensley, B.G. & Clarke, J. Take home lessons from studies of related proteins. Curr. Opin. Struct. Biol. 23, 66-74.

Wensley, B.G., Kwa, L.G., Shammas, S.L., Rogers, J.M., Browning, S., Yang, Z. & Clarke, J. (2012) Separating the effects of internal friction and transition state energy to explain the slow, frustrated folding of spectrin domains. Proc. Natl. Acad. Sci. USA 109, 17795-17799.

Borgia, M.B., Borgia, A., Best, R.B., Steward, A., Nettels, D., Wunderlich, B., Schuler, B. & Clarke, J. (2011) Single-molecule fluorescence reveals sequence-specific misfolding in multidomain proteins. Nature 474, 662-665.

Wensley, B.G., Batey, S., Bone, F.A.C., Chan, Z.M., Tumelty, N.R., Steward, A., Kwa, L.G., Borgia, A. & Clarke, J. (2010) Experimental evidence for a frustrated energy landscape in a 3-helix bundle protein family. Nature 463, 685-689.


Evolution of oligomeric state through allosteric pathways that mimic ligand binding
T Perica, Y Kondo, SP Tiwari, SH McLaughlin, KR Kemplen, X Zhang, A Steward, N Reuter, J Clarke, SA Teichmann – Science (2014) 346, 1254346
Interplay between partner and ligand facilitates the folding and binding of an intrinsically disordered protein.
JM Rogers, V Oleinikovas, SL Shammas, CT Wong, D De Sancho, CM Baker, J Clarke – Proceedings of the National Academy of Sciences of the United States of America (2014) 111, 15420
Allostery within a transcription coactivator is predominantly mediated through dissociation rate constants
SL Shammas, AJ Travis, J Clarke – Proceedings of the National Academy of Sciences of the United States of America (2014) 111, 12055
Coupled folding and binding of the disordered protein PUMA does not require particular residual structure.
JM Rogers, CT Wong, J Clarke – Journal of the American Chemical Society (2014) 136, 5197
Mechanism of assembly of the non-covalent spectrin tetramerization domain from intrinsically disordered partners
SA Hill, LG Kwa, SL Shammas, JC Lee, J Clarke – Journal of Molecular Biology (2014) 426, 21
The folding of a family of three-helix bundle proteins: spectrin R15 has a robust folding nucleus, unlike its homologous neighbours.
LG Kwa, BG Wensley, CG Alexander, SJ Browning, BR Lichman, J Clarke – Journal of molecular biology (2014) 426, 1600
Remarkably fast coupled folding and binding of the intrinsically disordered transactivation domain of cMyb to CBP KIX
SL Shammas, AJ Travis, J Clarke – J Phys Chem B (2013) 117, 13346
A mechanistic model for amorphous protein aggregation of immunoglobulin-like domains.
MB Borgia, AA Nickson, J Clarke, MJ Hounslow – Journal of the American Chemical Society (2013) 135, 6456
Folding and Binding of an Intrinsically Disordered Protein: Fast, but Not 'Diffusion-Limited'
JM Rogers, A Steward, J Clarke – Journal of the American Chemical Society (2013) 135, 1415
Biophysics: Rough passage across a barrier
B Schuler, J Clarke – Nature (2013) 502, 632
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Research Interest Group

Telephone number

01223 336426

Email address


Trinity Hall