Our research focuses on a class of proteins with very distinctive architectures, known as tandem-repeat proteins. Tandem-repeat proteins, which include ankyrin repeats, tetratricopeptide repeats, armadillo repeats and HEAT repeats, are frequently deregulated in human diseases including cancer and respiratory and cardiovascular diseases. The individual modules of repeat proteins 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 architecture; however, as suggested by their Slinky spring-like shapes, it is proposed 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 in and out of the nucleus. Thus, repeat proteins have been proposed to be a distinct structural class midway between globular structured proteins and intrinsically disordered proteins. The modular architecture of repeat proteins makes them uniquely amenable to the dissection of their biophysical properties as well as the rational redesign of these properties. We are interested in understanding how the process of folding and unfolding of this distinctive class of proteins directs their functions in the cell. We are also looking at small molecule and peptide-based approaches to target these proteins and their binding partners for therapeutic benefit. Lastly, we are exploring the fabrication of novel self-assembling repeat-protein nanomaterials. PhD projects will combine protein engineering with a range of biophysical and biochemical methods.
- Tsytlonok, M., Craig, P.O., Sivertsson, E., Serquera, D., Perrett, S., Best, R.B., Wolynes, P., Itzhaki, L.S. Complex energy landscape of a giant repeat protein. Structure 21: 1954-65 (2013). Previewed in “Falling Down: landscape and kinetics of one-dimensional protein folding”. Neira, J.L. Structure 21: 1905-7 (2013).
- Javadi Y., Itzhaki L.S. Tandem-repeat proteins: regularity plus modularity equals design-ability. Curr. Opin. Struct. Biol. 23: 622-31 (2013).
- Werbeck, N.D., Rowling, P.J., Chellamuthu, V.R., Itzhaki, L.S. Shifting transition states in the unfolding of a large ankyrin repeat protein. Proc. Natl. Acad. Sci. USA 105: 9982-7 (2008). See Commentary: 'The capillarity picture and the kinetics of one-dimensional protein folding'. Ferreiro, D.U. & Wolynes, P.G. Proc. Natl. Acad. Sci. USA 105: 1893-4 (2008).