Project No. 2471

STANDARD PROJECT

Primary Supervisor

Dr Sam  Thompson – University of Southampton

Co-Supervisor(s)

Dr Wei-Feng Xu – University of Kent

Dr Matthias Baud – University of Southampton

Summary

Intrinsically disordered proteins (IDPs) are a large class of functionally important biomolecules that are characterised by the occupation of a broad conformational ensemble.

Intrinsically disordered proteins (IDPs) are a large class of functionally important biomolecules that are characterised by the occupation of a broad conformational ensemble. Such a high degree of plasticity facilitates recognition of many protein and nucleic acid partners, making them key players in signalling and homeostasis. The penalty of such flexibility is that many diseases are associated with misfolding events in which a dysfunctional state is populated, including Alzheimer’s, Huntington’s, Parkinson’s, and type-II diabetes.

Understanding the basic science of healthy ageing – in which IDPs perform function without misfolding is critically important, but studying such highly dynamic and heterogenous species is challenging. An additional layer of complexity is added by the extensive posttranslational modification (PTM) observed. This ‘editing’ of protein structure, and thus editing of function, is a poorly understood regulation mechanism for IDPs, yet it is ubiquitous in healthy individuals.

To interrogate the fundamental relationships of IDP sequence/structure/function we will use chemical and peptide synthesis to prepare conformationally constrained homogenous peptide constructs and study their behaviour using biochemical and biophysical assays.

Specifically, this will involve: (i) the chemical synthesis of (a) unnatural amino acids allowing later peptide-stapling and conformational constraint, (b) amino acids bearing common PTMs (ST lab), (ii) peptide synthesis of IDP truncates using these amino acids (MB lab), (iii) conformational restriction of synthetic IDPs (ST lab), (iv) biochemical and biophysical assays (ThT, AFM, EM) of peptide aggregation kinetics, membrane leakage, toxicity, and aggregation (WFX lab), with IAPP and alpha synuclein as model systems in which we have expertise.

This work will improve our understanding of normal human function and thus healthy ageing. Moreover, it will demystify IDP behaviour and provide novel targets for therapeutic intervention.

The project would suit a candidate with a chemistry, or chemical biology background, who is keen to learn biochemical and biophysical techniques.