title: Understanding cell signalling systems: paving the way for new therapies.
abstract: The cell-to-cell signalling mechanisms of multi-cellular organisms orchestrate human development during embryogenesis and control homeostasis in adult tissues. These are mechanisms vital to human health and perturbation of cell-to-cell signalling is a contributing factor in many pathologies including cancer. The semaphorin cell guidance cues and their cognate plexin receptors exemplify a cell-to-cell signalling system for which insights into mechanistic principles are emerging. X-ray crystallographic data from Diamond beam lines have enabled us to probe the inner workings of semaphorin-plexin signalling to atomic-level resolutions. Importantly, we can complement protein crystallographic results with biophysical and cellular studies to dovetail structural information with functional impact. The signature seven-bladed β propeller 'sema' domain of the semaphorins forms a dimer; in contrast the equivalent domain in the plexins is monomeric. The generic architecture of a semaphorin-plexin complex is characterized by the dimeric semaphorin cross-linking two copies of the plexin receptor. For specific family members, the co-receptor neuropilin serves to bolster this architecture, but in all cases, the dimeric interaction lies at the core of the ligand receptor complex, providing the essential trigger for signalling.
authors.affiliation: Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK yvonne.jones@strubi.ox.ac.uk.
authors.forename: E Yvonne
authors.initials: EY
authors.lastname: Jones
mesh_terms: D000818:Animals; D015815:Cell Adhesion Molecules / Q000737:chemistry; D002450:Cell Communication; D018360:Crystallography, X-Ray; D006023:Glycoproteins / Q000737:chemistry; D006801:Humans; D008024:Ligands; D009419:Nerve Tissue Proteins / Q000737:chemistry; D039921:Neuropilins / Q000737:chemistry; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D039961:Semaphorins / Q000737:chemistry; D015398:Signal Transduction
chemical_list: D015815:Cell Adhesion Molecules; D006023:Glycoproteins; D008024:Ligands; D009419:Nerve Tissue Proteins; D039921:Neuropilins; D039961:Semaphorins; C091529:plexin
keywords: cell guidance cue; ligand–receptor complex; neuropilin; plexin; semaphorin