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Department of Chemistry

 
Portrait of jc162

PLEASE NOTE: Professor Clarke will be retiring at the end of September 2017 and therefore is not accepting any further applications.


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.

Publications

Promiscuous and Selective: How Intrinsically Disordered BH3 Proteins Interact with Their Pro-survival Partner MCL-1.
L Dahal, TOC Kwan, JJ Hollins, J Clarke
– Journal of molecular biology
(2018)
430,
2468
Folding and binding pathways of BH3-only proteins are encoded within their intrinsically disordered sequence, not templated by partner proteins
MD Crabtree, CATF Mendonça, QR Bubb, J Clarke
– J Biol Chem
(2018)
293,
9718
Protein-peptide association kinetics beyond the seconds timescale from atomistic simulations (vol 8, 2017)
F Paul, C Wehmeyer, ET Abualrous, H Wu, MD Crabtree, J Schöneberg, J Clarke, C Freund, TR Weikl, F Noé
– Nature Communications
(2018)
9,
1073
Conservation of Folding Mechanism in Cotranslational Folding of Titin I27
P Tian, A Steward, J Clarke, RB Best
– BIOPHYSICAL JOURNAL
(2018)
114,
593A
pKID Binds to KIX via an Unstructured Transition State with Nonnative Interactions.
L Dahal, TOC Kwan, SL Shammas, J Clarke
– Biophys J
(2017)
113,
2713
Promiscuous but selective: how intrinsically disordered BH3-only proteins regulate apoptosis through binding to BCL-2 like proteins
L Dahal, J Clarke
– PROTEIN SCIENCE
(2017)
26,
118
Disorder, Evolution and Plasticity: Biophysical Signatures of the Arbitration of Apoptosis
B Wicky, T Kwan, J Clarke
– PROTEIN SCIENCE
(2017)
26,
122
Phosphorylation of the IDP KID Modulates Affinity for KIX by Increasing the Lifetime of the Complex
L Dahal, SL Shammas, J Clarke
– Biophys J
(2017)
113,
2706
Protein-peptide association kinetics beyond the seconds timescale from atomistic simulations.
F Paul, C Wehmeyer, ET Abualrous, H Wu, MD Crabtree, J Schöneberg, J Clarke, C Freund, TR Weikl, F Noé
– Nature Communications
(2017)
8,
1095
Affinity of IDPs to their targets is modulated by ion-specific changes in kinetics and residual structure.
BIM Wicky, SL Shammas, J Clarke
– Proceedings of the National Academy of Sciences of the United States of America
(2017)
114,
9882
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Research Group

Research Interest Group

Telephone number

01223 336426

Email address

jc162@cam.ac.uk