Defining the Mechanisms Underlying Tandem Repeat Protein Functions

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Almost 20% of the proteins estimated to be encoded in the human genome contain small structural units repeated multiple times in tandem. Many of these so-called ?tandem repeat proteins? are dys-regulated in cancers and neurodegenerative diseases, two of the biggest medical problems facing our ageing population. They are also implicated in a plethora of other disorders including inflammatory, cardiovascular and respiratory diseases. In order to find new ways to treat these diseases we need to understand the basic mechanisms underlying repeat protein functions. Repeat protein structures are distinct from the more commonly studied ?globular? (spherical-shaped) proteins. The individual modules of a repeat protein stack in a linear fashion to produce highly elongated, superhelical structures, thereby presenting an extended scaffold for molecular recognition. The term ?scaffold? implies a rigid structure; however, as suggested by their Slinky spring-like shapes, it is likely that repeat arrays utilise much more dynamic and elastic modes of action. For example: stretching and contraction motions to regulate the activity of a bound enzyme; reversible nanosprings to operate ion channels; proteins that wrap around their cargoes to transport them into the nucleus of the cell. We propose to assemble a new toolbox of biophysical and single molecule techniques to overcome the challenges specific to these proteins and to address the following key questions about their unique architectures: (1) How do the properties of the individual modules contribute to the behaviour of the array as a whole? What are the motions of a repeat protein under physiological conditions and how do these motions enable it to carry out its function? (2) Repeat proteins have highly symmetrical structures and this means that they behave in a non-homogeneous way; can we quantify and characterize each species within this heterogeneous mix? (3) What are the mechanical properties of repeat proteins and how do they control function? (4) What is the pathway by which a repeat protein recognises its binding partner? (5) Finally, we will exploit what we learn to then ask how protein stability is regulated in the cell ? specifically what features of a protein?s structure determine its susceptibility to the cell?s protein degradation machinery known as the ?proteasome? which removes unwanted proteins once they have carried out their functions? The findings of our research will pave the way for future development of drug-like molecules with which we aim to manipulate the behaviour of tandem repeat proteins for therapeutic benefit.