(A) Repulsive Guidance Molecule (RGM) in complex with its receptor NEO1 (Science 2013). (B) RGM-NEO1-BMP complex, revealing that RGM bridges the NEO1 and BMP morphogen pathways (NSMB 2015).Image 1 of 3
|Crystal structures of the GPCR and Hh signal transducer Smoothened bound to the agonist cholesterol and the anti-cancer drug vismodegib, respectively (Nature 2016, ELife 2016).|
Professor of Structural Biology
Structural studies on Morphogen Signalling
A handful of secreted morphogen signalling molecules, acting in a spatial and gradient-dependent manner, orchestrate the development of multicellular organism. Morphogen dysfunction leads to a range of diseases and defects in adult stem cell populations. Their importance in human disease has become increasingly clear over the past decade: dysfunctions of the pathways are known to lead to severe developmental and neurological diseases, and cancer.
Our group seeks to generate mechanistic insights relevant to disease and embryonic development focusing on two fundamental morphogen signalling systems: the Hedgehog (Hh) and the bone morphogenetic protein (BMP) pathways. Extracellular Hh and BMP signals are mediated by various cell surface receptor molecules. We aim to unravel the molecular mechanisms underlying Hh and BMP morphogen gradient formation and signal transduction across the cell membrane.
To achieve this, we are using structural biology techniques such as X-ray crystallography and cryo electron microscopy to obtain molecular snapshots of Hh and BMP interactions with other proteins. We combine atomic details from in vitro structural and biophysical studies on single molecules with analyses of Hh and BMP function in living cells. Our findings will be integrated with those from developmental and cellular biologists to provide a deeper understanding of these pathways and explore translational opportunities, for example in anti-cancer therapy.
Glypicans shield the Wnt lipid moiety to enable signalling at a distance.
McGough IJ. et al, (2020), Nature
Cholesterol accessibility at the ciliary membrane controls Hedgehog signaling.
Kinnebrew M. et al, (2019), eLife, 8
The morphogen Sonic hedgehog inhibits its receptor Patched by a pincer grasp mechanism.
Rudolf AF. et al, (2019), Nat Chem Biol
iASPP mediates p53 selectivity through a modular mechanism fine-tuning DNA recognition.
Chen S. et al, (2019), Proc Natl Acad Sci U S A, 116, 17470 - 17479
Structures of vertebrate Patched and Smoothened reveal intimate links between cholesterol and Hedgehog signalling.
Kowatsch C. et al, (2019), Curr Opin Struct Biol, 57, 204 - 214