Molecular mechanisms of Repulsive Guidance Molecule (RGM) action (360G-Wellcome-097301_Z_11_Z)

Repulsive Guidance molecules (RGMs), a family of membrane-anchored glycoproteins, are involved in two key signalling pathways: the Neogenin (NEO1) [1] and bone morphogenetic protein (BMP) [2] pathways. RGMs control and fine-tune a wide range of functions from neural development [3] to leukocyte migration [4], and are implicated in several severe diseases, for example juvenile hemochromatosis [5,6] and cancer [7]. The aim of this research project is to fully characterise the actions of RGMs at the membrane interface with both of these pathways. This will involve biophysical and cell-based measurements to build on a crystal structure of RGM bound to BMP (obtained in my first rotation project) to understand how RGMacts as an activator in this pathway. It will also involve crystallisation of complexes involving proteins from both pathways to study how the two pathways are connected. I will also work towards crystallising the full-length type I membrane protein BMP-receptors to gain insight into how the signal is transmitted across the membrane. This will be supported by functional studies using fluorescence techniques, biophysical and cellular analyses.