Researchers in Structural Biology (STRUBI) at the Wellcome Trust Centre for Human Genetics have demonstrated a new signalling mechanism that operates between cells, and shown how it might be manipulated as a therapy for cancer.
Proteins on the surfaces of cells interact with receptors on other nearby cells as the body develops, grows and maintains itself. This exchange of signals either attracts or repels the migrating cells, and if the process goes wrong it can lead to cancers. Elena Seiradake worked with STRUBI co-director Yvonne Jones and colleagues in Oxford and at the Max Planck Institute of Neurobiology in Germany to look at a family of receptors called Ephs, and the protein family that binds to them, called ephrins.
Using X-ray crystallography to reveal the structure of protein-receptor complexes, they have found that when ephrins bind closely related but not identical Ephs, these receptors cluster together in different ways to form small groups or larger arrays. The team have also demonstrated these same clustering properties in situ at the cell surface using super resolution light microscopy (at the Wellcome Trust-funded Micron Oxford Advanced Bioimaging Unit). Previous work has shown that in some instances the degree of clustering is related to malignancy in breast cancer.
In a paper just published in the journal Nature Structural Molecular Biology, the researchers show that by manipulating the parts of the Eph molecule that are involved in clustering, they can switch the receptor’s effect from attraction to repulsion or vice-versa. This suggests a new way of targeting the interaction between Ephs and ephrins as a possible cancer therapy.
‘The Ephs may exemplify a new mechanism’, says Professor Jones, ‘whereby a relatively small number of distinct receptors can control the vast number of diverse signalling processes associated with the complexity we find in higher organisms.’
Elena Seiradake, Andreas Schaupp, Daniel del Toro Ruiz, Rainer Kaufmann, Nikolaos Mitakidis, Karl Harlos, A Radu Aricescu, Rüdiger Klein & E Yvonne Jones, Structurally encoded intraclass differences in EphA clusters drive distinct cell responses. Nat Struct Mol Biol. 2013;20: doi:10.1038/nsmb.2617. Published online 30 June 2013.