Molecular mechanisms in the nervous and vascular systems
Co-workers: Verity Jackson, Maria Carrasquero Ordaz and Liam Argent
We study cell guidance receptors involved in brain development, blood vessel formation and cancer. Much like a navigation system, these proteins direct migrating cells and axons through the developing body. This gives rise, for example, to the neural networks that underlie the functions of the brain, and the vascular network that maintains blood flow. In cancers, cell guidance often fails to function properly and as a result cells behave and spread aberrantly. Therefore understanding how guidance receptors work also provides insights into cancer development.
We use a range of powerful and cutting-edge techniques, especially X-ray crystallography, advanced cell biology assays, confocal and super resolution microscopy. Combining multiple techniques allows us to understand how cell guidance receptors function on the molecular, cellular and tissue levels.
- Jackson VA, Mehmood S, Chavent M, Roversi P, Carrasquero M, del Toro D, Seyit-Bremer G, Ranaivoson FM, Comoletti D, Sansom MSP, Robinson CV, Klein R, Seiradake E. Super-complexes of adhesion GPCRs and neural guidance receptors. Nature Communications 2016 Apr 19 doi:10.1038/ncomms11184
- Jackson VA, del Toro D, Carrasquero M, Roversi P, Harlos K, Klein R, Seiradake E. Structural basis of Latrophilin-FLRT interaction. Structure 2015 Apr 7;23(4):774-81.
- Seiradake E, del Toro D, Nagel D, Cop F, Haertl R, Ruff T, Seyit-Bremer G, Harlos K, Border EC, Acker-Palmer A, Jones EY, Klein R. FLRT Structure: Balancing Repulsion and Cell Adhesion in Cortical and Vascular Development. Neuron 2014 Oct 22;84(2):370-85.
- Kaufmann R, Schellenberger P, Seiradake E, Dobbie IM, Jones EY, Davis I, Hagen C, Grunewald K. Super-resolution microscopy using standard fluorescent proteins in intact cells under cryo-conditions. Nano Lett. 2014 Jul 9;14(7):4171-5.
- Seiradake E, Schaupp A, del Torro Ruiz D, Kaufmann R, Mitakidis N, Harlos K, Aricescu AR, Klein R, Jones EY. Structurally encoded intraclass differences in EphA clusters drive distinct cell responses. Nat Struct Mol Biol 2013 Aug;20(8):958-64.
- Seiradake E, Coles CH, Perestenko PV, Harlos K, McIlhinney RA, Aricescu AR, Jones EY. Structural basis for cell surface patterning through NetrinG-NGL interactions. EMBO J. 2011 Sep 23;30(21):4479-88.
- Seiradake E, Harlos K, Sutton G, Aricescu AR, Jones EY.An extracellular steric seeding mechanism for Eph-ephrin signaling platform assembly. Nat Struct Mol Biol. 2010 Apr;17(4):398-402.
Figure 1. Isolated fragments of these protein crystals were used for high resolution X-ray diffraction data collection at the Diamond Light Source near Oxford.
Figure 2. Crystallography data reveals how the guidance receptor Unc5 (shades of blue) binds its ligand FLRT (orange).
Figure 3. Study of cell surface receptor clusters using super resolution microscopy (dSTORM). Collaboration Kaufmann.
Figure 4. Automated data analysis of a growth cone collapse assay using thalamic explants. Non-collapsed growth cones are encircled and marked with white arrow heads (right panel). Collaboration del Toro Ruiz/Klein.
Graduate Student and Postdoctoral Positions: Enquiries with CV welcome