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Protein folding and disulphide bond formation

The group's core research interest is the process of folding and modifcation of proteins in the secretory pathway, particularly the formation of disulphide bonds which is facilitated by the folding catalyst and chaperone protein disulphide isomerase (PDI).

Currently we are pursuing three strands of work on this topic:

  • In work funded by the Wellcome Trust and supported by studentships from various sources, we are determining the functional, structural and dynamic properties of human PDI and various members of the human PDI family. We are interested in the structural basis of specificity between different members of the PDI family, in details of the interactions between PDI and its substrates and partner proteins, and in how these interactions may be facilitated by mobility within and between domains of PDI and its homologues. This work involves collaboration with Drs. Richard Williamson and Mark Howard (University of Kent), Prof Hermann Schindelin (Wuerzburg) and Prof CC Wang (Institute of Biophysics, Beijing).
  • In collaboration with theoreticians, we are also exploring rapid computational methods for investigating the flexibility and dynamics of proteins and applying these to PDI and its homologues. The work involves ‘flexibility analysis’ which requires orders of magnitude less computer power than molecular dynamics, but has been spectacularly successful in predicting unexpected experimental characteristics of the dynamics of PDI and its homologues. The work involves collaborations with Prof. Rudo Roemer (Physics, Warwick), Dr. Stephen Wells (Physics, Bath) and Prof. Saraswathi Vishveshwara (Indian Institute of Science, Bangalore).
  • In work funded by BBSRC, we are aiming to modify microorganisms to make them more effective host cells for the production of high-value disulphide-bonded proteins for pharmaceutical or diagnostic applications. This work involves drawing on our knowledge of how such proteins are made and exported in mammalian cells and using these insights to engineer the cellular machinery of bacteria to equip them with the capability to fold such proteins within the bacterial cytoplasm and then export them efficiently using the bacterial Tat machinery. This work (joint with Prof Colin Robinson) involves collaborations with Profs. Eli Keshavarz-Moore (University College London) and Lloyd Ruddock (University of Oulu, Finland), and with industrial partners.

 

Current Members of Group

Dr Narinder Sanghera
John Blood
Jack Heal
Kelly Walker

Recent members of the Group:
Dr Katrine Wallis (post-doc 2004-20012, now Lecturer, Coventry University)
Dr Sihong Chen (post-doc 2008-2009, now industrial researcher, Oxford)
Dr Ateesh Sidhu (PhD 2004-2008, now post-doc researcher, Cancer Research UK)
Dr Nader Amin (PhD 2004-2008, now industrial researcher, Cambridge)
Dr Alistair Irvine (PhD 2006-2010, now post-doc researcher, NTU Singapore)
Dr Michael Caves (PhD 2007-2011, now industrial researcher, Wokingham)