Science for Health
Nuclear magnetic resonance (NMR) spectroscopy provides a valuable means to probe the three dimensional structure, dynamic characteristics and binding properties of biological macromolecules. Our group employs state-of-the-art methods in NMR, combined with other biochemical and biophysical approaches, to probe the nature and interactions of proteins implicated in fundamental cellular and organismal processes. Currently our interests include the activation of death receptor signalling cascades in apoptosis, limb regeneration in the adult newt, the regulation of phospholipases by small G proteins, and the basis of antigen recognition underlying Hughes Syndrome.
In multi-cellular organisms the life, differentiation, proliferation and death of individual cells is highly regulated by the action of both extrinsic soluble proteins and other chemical factors, and by contacts between cells mediated by molecules tethered to the cell surface. The interaction of the exogenous components with cell surface receptors is communicated to the inner workings of the individual cells by the specific enzymatic action of the cytoplasmic component of the receptor leading to the chemical modification or conformational alteration of either the receptor or attached proteins. The modified protein can then either alter its own function or specifically recruit one or a number of diffusible downstream proteins that in turn are chemically modified or are induced to alter conformation so as to transfer the chemical signal that the receptor has been activated. In this manner signals are transduced within cells. Often the pattern of the pathways is multiply bifurcated and includes regulatory feedback loops. Our understanding of these signalling networks is growing all the time, and this research activity provides the framework within which many drug discovery programmes are being pursued. We aim to contribute to this field through the combined structural, functional and biophysical analysis of the interactions between cell-surface receptors, their ligands and downstream signalling partners.
One focus of the group is a subset of cell surface receptors known as the death receptor superfamily. The ligands to these receptors have the ability to induce programmed cell death (‘apoptosis’) pathways that lead to the elimination of the targeted cells. Regulated cell death is important for homeostasis of the immune system and the development of organs and tissues. When apoptosis pathways become dysfunctional this can contribute to the development and maintenance of autoimmune disease and cancer. Curiously these death receptors can also signal cell survival under specific conditions. We are applying state-of-the-art methods in NMR to investigate the 3D structure and interactions of the cytoplasmic ‘death’ domains of the death receptors with the apical components of the apoptotic signalling cascade.
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A structure-based phylogenetic tree of death receptor and signalling protein ‘death domains’.
We have recently investigated the 3D solution structure and phylogeny of the protein Prod-1 which has been recognised as an important marker of the positional identity of the blastema that forms at an amputation site in the adult newt. The blastema is a structure that when transplanted gives rise to regeneration of the missing limb parts. Our analysis indicates that, whilst superficially similar to well known mammalian three-finger superfamily proteins, Prod-1 is nevertheless restricted to salamanders. This result may have important implications for realisation of the promise of this classic example of appendage regeneration for development of medical applications in humans. In ongoing work we are aiming to characterise other novel proteins implicated in newt limb regeneration and their interactions with more conserved components of cell signalling systems.
Ribbon and bundle representation of the 3D solution structure of Prod-1.
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