School of Biosciences

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Dr Ben Goult

Senior Lecturer in Biochemistry

School of Biosciences, Stacey G14

 

Career

  • 1995-1998 University of Sheffield: BSc(Hons) Biochemistry 2:1
  • 1998-2002 UMIST: PhD in Biological Science
  • 2003-2005 University of Manchester: Research Associate
  • 2005-2006 AstraZeneca Alderley Park: Senior Physical Scientist
  • 2006-2012 University of Leicester: Research Associate
  • 2012-2014 University of Leicester: Research Fellow

Dr Ben Goult obtained his first degree in Biochemistry at the University of Sheffield in 1998, before embarking on a PhD in the labs of Dr Tim Norwood (University of Leicester) and Professor Lu-Yun Lian (University of Leicester/ Manchester) developing NMR based approaches for detecting small molecule binding to target proteins, a first step in drug discovery. Following a 2year postdoctoral position at the University of Manchester he moved to AstraZeneca Alderley Park as a Senior Physical Scientist.

In 2005, Ben returned to Leicester to work with Professor David Critchley on the proteins that regulate cell adhesion and migration, in particular the FERM domain containing proteins talin and kindlin; key players in integrin mediated adhesion. In 2010, he was awarded a Wellcome Trust Project Grant to work on another FERM domain protein, IDOL, an E3-ligase that regulates levels of the LDL-Receptor via ubiquitination. IDOL is a potential drug target for the treatment of hypercholesterolemia.

Ben joined the School of Biosciences in August 2014 where his research group specializes in the structural and biochemical studies of cell-extracellular matrix (ECM) adhesion complexes.

Ben is a member of the Protein Form and Function Group.

ORCID: 0000-0002-3438-2807

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Also view these in the Kent Academic Repository

Article
Collier, M. et al. (2017). Investigation of the filamin-A dependent mechanisms of tissue factor incorporation into microvesicles. Thrombosis and Haemostasis [Online]. Available at: https://th.schattauer.de/index.php?id=3864&L=1&schattauer_issue%5BissueId%5D=2547&schattauer_issue%5BmanuscriptId%5D=27993&schattauer_issue%5BmanuscriptMode%5D=show&cHash=3d36e7b20d08ffe5f1081eea176fcbbf.
De Franceschi, N. et al. (2017). ProLIF: a quantitative assay for investigating integrin cytoplasmic protein interactions and synergistic membrane effects on proteoliposomes. BioRxiv [Online]. Available at: https://doi.org/10.1101/209262.
Kumar, A. et al. (2016). Talin tension sensor reveals novel features of focal adhesion force transmission and mechanosensitivity. Journal of Cell Biology [Online] 213:371-383. Available at: http://dx.doi.org/10.1083/jcb.201510012.
Qi, L. et al. (2016). Talin2-mediated traction force drives matrix degradation and cell invasion. Journal of Cell Science [Online] 129:3661-3674. Available at: http://dx.doi.org/10.1242/jcs.185959.
Bouchet, B. et al. (2016). Talin-KANK1 interaction controls the recruitment of cortical microtubule stabilizing complexes to focal adhesions. eLife [Online] 10:1-42. Available at: http://dx.doi.org/10.7554/eLife.18124.
Yao, M. et al. (2016). The mechanical response of talin. Nature Communications [Online] 7:1-11. Available at: http://dx.doi.org/10.1038/ncomms11966.
Zacharchenko, T. et al. (2016). LD Motif Recognition by Talin: Structure of the Talin-DLC1 Complex. Structure [Online]:1-13. Available at: http://www.dx.doi.org/10.1016/j.str.2016.04.016.
Yan, J. et al. (2015). Talin Dependent Mechanosensitivity of Cell Focal Adhesions. Cellular and Molecular Bioengineering [Online] 8:151-159. Available at: http://dx.doi.org/10.1007/s12195-014-0364-5.
Skinner, S. et al. (2015). Structure calculation, refinement and validation using CcpNmr Analysis. Acta Crystallographica Section D-Biological Crystallography [Online] 71:154-161. Available at: http://dx.doi.org/10.1107/S1399004714026662.
Villari, G. et al. (2015). A direct interaction between fascin and microtubules contributes to adhesion dynamics and cell migration. Journal of Cell Science [Online]:1-32. Available at: http://dx.doi.org/10.1242/jcs.175760.
Atherton, P. et al. (2015). Vinculin controls talin engagement with the actomyosin machinery. Nature Communications [Online] 6:1-12. Available at: http://dx.doi.org/10.1038/ncomms10038.
Ellis, S. et al. (2014). The Talin Head Domain Reinforces Integrin-Mediated Adhesion by Promoting Adhesion Complex Stability and Clustering. PLoS Genetics [Online] 10:e1004756. Available at: http://dx.doi.org/10.1371/journal.pgen.1004756.
Yao, M. et al. (2014). Mechanical activation of vinculin binding to talin locks talin in an unfolded conformation. Scientific reports [Online] 4:4610. Available at: http://dx.doi.org/10.1038/srep04610.
Evans, S. et al. (2014). The ansamycin antibiotic, rifamycin SV, inhibits BCL6 transcriptional repression and forms a complex with the BCL6-BTB/POZ domain. PloS one [Online] 9:e90889. Available at: http://dx.doi.org/10.1371/journal.pone.0090889.
Goult, B. et al. (2013). Structural studies on full-length talin1 reveal a compact auto-inhibited dimer: implications for talin activation. Journal of structural biology [Online] 184:21-32. Available at: http://dx.doi.org/10.1016/j.jsb.2013.05.014.
Dhani, D. et al. (2013). Mzt1/Tam4, a fission yeast MOZART1 homologue, is an essential component of the γ-tubulin complex and directly interacts with GCP3(Alp6). Molecular biology of the cell [Online] 24:3337-3349. Available at: http://dx.doi.org/10.1091/mbc.E13-05-0253.
Watkins, R. et al. (2013). A novel interaction between FRMD7 and CASK: evidence for a causal role in idiopathic infantile nystagmus. Human molecular genetics [Online] 22:2105-2118. Available at: http://dx.doi.org/10.1093/hmg/ddt060.
Goult, B. et al. (2013). RIAM and vinculin binding to talin are mutually exclusive and regulate adhesion assembly and turnover. The Journal of biological chemistry [Online] 288:8238-8249. Available at: http://dx.doi.org/10.1074/jbc.M112.438119.
Ellis, S. et al. (2013). Talin autoinhibition is required for morphogenesis. Current biology [Online] 23:1825-1833. Available at: http://dx.doi.org/10.1016/j.cub.2013.07.054.
Phelan, M. et al. (2012). The structure and selectivity of the SR protein SRSF2 RRM domain with RNA. Nucleic acids research [Online] 40:3232-3244. Available at: http://dx.doi.org/10.1093/nar/gkr1164.
Bate, N. et al. (2012). Talin contains a C-terminal calpain2 cleavage site important in focal adhesion dynamics. PloS one [Online] 7:e34461. Available at: http://dx.doi.org/10.1371/journal.pone.0034461.
Banno, A. et al. (2012). Subcellular localization of talin is regulated by inter-domain interactions. The Journal of biological chemistry [Online] 287:13799-13812. Available at: http://dx.doi.org/10.1074/jbc.M112.341214.
Bouaouina, M. et al. (2012). A conserved lipid-binding loop in the kindlin FERM F1 domain is required for kindlin-mediated αIIbβ3 integrin coactivation. The Journal of biological chemistry [Online] 287:6979-6990. Available at: http://dx.doi.org/10.1074/jbc.M111.330845.
Clayton, J. et al. (2011). The 1H, 13C and 15N backbone and side-chain assignment of the RRM domain of SC35, a regulator of pre-mRNA splicing. Biomolecular NMR assignments [Online] 5:7-10. Available at: http://dx.doi.org/10.1007/s12104-010-9254-5.
Calkin, A. et al. (2011). FERM-dependent E3 ligase recognition is a conserved mechanism for targeted degradation of lipoprotein receptors. Proceedings of the National Academy of Sciences of the United States of America [Online] 108:20107-20112. Available at: http://dx.doi.org/10.1073/pnas.1111589108.
Showing 25 of 43 total publications in KAR. [See all in KAR]
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Research Interests

  • Cell-extracellular matrix (ECM) adhesion complexes, FERM domains
  • Structural Biology: NMR Spectroscopy, X-Ray Crystallography and Small Angle X-Ray Scattering (SAXS)

My research involves the use of biophysical techniques to understand the structure and function of proteins that are involved in the process of Cell-extracellular matrix (ECM) adhesion. Such adhesion proteins are increasingly recognised as potential targets for therapeutic intervention in a range of pathologies including immune and vascular disorders, blood clotting, skin blistering, wound healing and cancer.

Talin, a master mechanosensor regulating cell-matrix adhesion assembly

Our recent structural characterisation of talin (Goult et al. JBC 2013) has provided new insights into how talin performs its multiple different roles and we are now using a combination of biochemical and biophysical techniques to investigate physiologically relevant, force dependent, conformational changes in talin that regulate its function.

fig 1

Fig.1 Model of talin showing the structures of all 18 domains

The talin rod is comprised of 4- and 5-helix bundles, each with distinct mechanical and ligand binding profiles. Each domain has a unique binding profile and can be generally defined as; (i) mechanically sensitive, (ii) mechanically insensitive, (iii) mechanically sensitive but protected from mechanical force, (iv) mechanically sensitive only under certain conditions. The arrangement of these domains has profound implications for how talin functions as a molecular biosensor.


 

Talin has a large number of binding partners including RIAM, vinculin, actin, integrin, synemin, DLC1 and also talin, each binding to different regions of the rod. As such, this knowledge of the domain structure of talin is enabling us to study these interactions and gain a better understanding of the complex roles talin plays in regulating cellular adhesion to the extracellular matrix.

fig 2

Fig.2 Talin changes binding partners in response to force induced conformational change

Stretching single Talin molecules.
Rapid progress in single-molecule force manipulation technologies have made it possible to directly study the impact of mechanical force on talin conformations and its interactions with other signaling proteins.By using magnetic tweezers we are able to stretch single talin molecules and explore their structural and biochemical properties as a function of force.

 

slide

Fig. 3 A single talin molecule is attached between a surface and a paramagnetic bead. Forces are applied to the bead by a pair of permanent magnets. The force dependence of the interactions between talin and its ligands can then be studied in the absence and presence of force

Such techniques are enabling us to study the mechanical properties of each individual talin domain and characterise force dependent protein interactions

 

 

 

 

 

 

 

 

 

 

 

figure

Fig.4 Stretching a single talin molecule. (a) the compact N-terminal fragment of the talin rod contains three domains, R1, R2 and R3. (b) The three helical bundles unfold in three distinct steps consistent with the domains unfolding independently. (c) A stabilising mutant in R3 (IVVI) shifts the initial unfolding event confirming R3 as the initial unfolding mechanosensor.

 

We are using this approach to fully characterise how talin functions as a mechanosensor.

 

 

 

 

 

 

 

 

 

 

 

Pubmed Link

Google Scholar

If you are interested in joining the group then please contact:
Dr Ben Goult

Collaborations:

Prof. Mark Ginsberg, UCSD (San Diego)
Guy Tanentzapf, UCB (Vancouver)
Jie Yan and Mike Sheetz, Mechanobiology Institute (Singapore)

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Year 1

  • BI301 Enzymes and Introduction to Metabolism

Final Year

  • BI602 Cellular Communication 1
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Committees

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Enquiries: Phone: +44 (0)1227 823743

School of Biosciences, University of Kent, Canterbury, Kent, CT2 7NJ

Last Updated: 27/09/2017