EPHR SIGNALING · Proteins in cell-to-cell communication: the Eph receptors and their ephrin ligands
FP7 — People (Marie Curie Actions)
- Duration
- 2010-05-01 → 2012-04-30
- EU contribution
- €172,435
- Participants
- 1
- Scheme
- MC-IEF
Lines connect the coordinator with its partners.
Results in brief
Proteins in cell-to-cell communication: the Eph receptors and their ephrin ligands
Project context and objectives Erythropoetin-producing hepatoma (Eph) receptors are cell surface protein tyrosine kinases mediating cell-cell communication. They direct key processes during development and repair of the nervous system, blood vessel formation, insulin secretion, immune system function, intestinal homeostasis and bone tissue integrity. Upon binding to their ligand, activated Eph receptors form signalling clusters. Work performed We set out to study the architecture of such clusters and solved crystal structures of the full ectodomain of human EphA2 (eEphA2), alone and with the receptor-binding domain of the ligand ephrinA5 (ephrinA5RBD). Unliganded eEphA2 forms linear arrays of staggered parallel receptors that involve two patches of residues conserved across A-class Ephs. eEphA2-ephrinA5RBD forms a more elaborate assembly, the interfaces of which include the same conserved regions on eEphA2, but are rearranged to accommodate ephrinA5RBD. Cell surface expression of mutant EphA2s demonstrated that these interfaces are critical for localisation at cell-cell contacts and activation-dependent degradation. Main results Our results suggest a 'nucleation' mechanism whereby a limited number of ligand-receptor interactions seed an arrangement of receptors which can propagate into extended signalling arrays. This work was published in Seiradake et al. Nat. Struct. Mol. Biol. 2010 (see also http://www.nature.com/nsmb/journal/v17/n4/full/nsmb.1782.html for more information). Our subsequent work has extended these studies to additional ephrin-Eph complexes and is currently at the stage of functional analysis so as to validate proposed molecular mechanisms in the cellular context.
Data: CORDIS, © European Union
Project objective
I propose to solve the structure of Eph receptors and their ephrin ligands in an effort to gain a complete understanding of their functions and acquire knowledge and training to advance my career prospects. These proteins are located at the outer membrane of cells. When they bind, they transmit a signal into the cell that carries them, providing a means of cell-to-cell communication. They control vital aspects of life where cells have to communicate with each other, such as brain development, blood vessel formation, insulin secretion, and they play a role in many cancers. Studying their structure and signalling mechanism reveals their role in these biological processes, and provides fundamental knowledge for medical purposes. Eph receptors are type I transmembrane proteins and consist of a number of discrete domains. The crystal structures of single Eph receptor and ephrin domains are known. However, the central question of how the Eph receptor transmits a signal from the exterior of the cell into the cell interior remains unsolved. My objective is to tackle this fundamental question by finding out how the individual Eph receptor domains are arranged with respect to each other, how the binding of ephrin ligand affects this configuration, and how it relates to Eph receptor signalling. In the short term, I will use structural biology tools to examine the structure of the entire extracellular part of an Eph receptor. I have already produced preliminary data to validate the feasibility of this approach. In the medium term I will examine the structure of the extracellular part of the Eph receptor bound to an ephrin ligand. I will interpret the structural information I derive to study Eph receptor and ephrin functions. In the long term I will design and apply experimental protocols to characterize the structure of the entire transmembrane Eph receptor. This project constitutes a stepping stone from my early research to a mature and long term career in science.
Original text from CORDIS.
Participants
- THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD · OxfordCoordinatorUnited Kingdom
Links
Data: CORDIS, © European Union