Understanding amyloid assembly mechanisms

A key problem in life sciences research is to understand the role of transient protein-protein interactions (PPIs) of intrinsically disordered regions (IDRs) – this would allow identification of the transient intermediates that play key roles in the folding and aggregation of functional proteins to illuminate our understanding of disease development (e.g. aggregation in amyloid disease) and contribute towards the development and manufacture of bespoke materials. Whilst mechanistic studies in organic chemistry are well established, the molecular mechanisms of such self-assembly reactions are less well explored. Ongoing studies in our group have focussed on developing integrated methods that comprise a suite of biochemical and computational methods together with state-of the art mass-spectrometry to study amyloid assembly. At the core of this approach is the cross-linking of diazirines which upon excitation generate highly reactive carbenes to encode non-covalent structure in the resultant cross-linked peptides. These approaches have recently been harnessed to provide, for the first time, an analysis of the structural mechanism of surface-catalyzed secondary nucleation in amyloid assembly. Alongside these efforts ongoing research is focussed on developing chemical probes that can be used to understand amyloid assembly reactions and providing starting points for therapeutics development. 

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Key Papers

E. E. Cawood, N. Guthertz, J. Ebo, T. Karamanos, S. E. Radford FRS, A. J. Wilson: Modulation of Amyloidogenic Protein Self-Assembly Using Tethered Small Molecules, J. Am. Chem. Soc., 2020142 (49), 20845–20854. View Paper

S. J. Bunce, Y. Wang, K. L. Stewart, A. E. Ashcroft, S. E. Radford, C. K. Hall,  A. J. Wilson: Molecular Insights into the surfacecatalyzed secondary nucleation of Amyloid-β40 (Aβ40) by the peptide fragment Aβ16-22, Sci. Adv., 2019, 5, 6. View Paper.

Y. Wang, S. J. Bunce, S. E. Radford, A. J. Wilson, S. Auer, C. K. Hall: Thermodynamic Phase Diagram of Amyloid-β (16-22) Peptide, Proc. Natl. Acad. Sci. USA, 2019, 116, 2091-2096. View Paper.

G.W. Preston, S. E. Radford, A. E. Ashcroft, A. J. Wilson: Analysis of Amyloid Nanostructures Using Photo-Crosslinking: In Situ Comparison of Three Widely Used Photo-Crosslinkers, ACS Chem. Biol., 2014, 9, 761–768. View Paper.

G.W. Preston, S. E. Radford, A. E. Ashcroft, A. J. Wilson: Covalent cross-linking within supramolecular peptide structures, Anal. Chem., 2012, 84, 6790–6797. View Paper.

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Collaborators

Sheena Radford (University of Leeds), Eric Hewitt (University of Leeds), Carol Hall (North Carolina State University, USA) 

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Current and Recent Funding 

EPSRC EP/N035267/1Designer Chemistry to Probe Supramolecular Assembly Mechanism and Function’   

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Related Areas: 

Chemical protein labelling fostructural proteomics and interactome analyses 

New methods to modulate protein-protein interactions for drug discovery