Postgraduate research opportunities Development of mass spectrometry methods to investigate conformations and complexes of proteins relating to health and disease

It was long thought that each protein has a specific 3-dimensional fold or conformation that is required for it to carry out its function in the cell. More recently, it has been discovered that a subset of proteins, called intrinsically disordered proteins (IDPs), exist in a range of conformations under physiological conditions, and interconvert rapidly between these conformations. IDPs are heavily involved in cell signalling networks that control cellular replication and are therefore overrepresented in diseases such as cancer. They are therefore often considered attractive drug targets, but their dynamic behaviour makes them difficult to study with traditional structural biology methods. New techniques are required to characterise these proteins, leading to better understanding of their behaviour which will result in increased drugability of IDPs and hence better therapies for disease.

Ion mobility mass spectrometry (IMMS) is a widely applicable, low-resolution method that measures the range of conformations in which an IDP exists, and can report on any preference of the IDP for a compact or extended shape. The IDP’s response to different solution conditions such as salt concentration or pH can be measured, and its interaction modes with cellular binding partners can be delineated. For example, it can be deduced whether the IDP folds upon binding, or retains dynamic behaviour as part of the protein complex. Moreover, the structural effect of small molecule inhibitors or modulators on the IDP can be uncovered.

During this project, IMMS will be used to characterise the conformational spread of an IDP and interrogate how it interacts with its binding partner. Methods will subsequently be developed to screen libraries of small molecules to search for compounds that affect the conformational distribution of the IDP, and hence its ability to bind to its partner. These molecules will be used as chemical probes to delineate the effect of different conformational groups on the function of the IDP in question, for example, which conformation is required for protein complex formation.

The project will be based in the lab of Dr Rebecca Beveridge, which houses excellent IMMS infrastructure.