A single protein family—the semaphorins—controls whether a cell sticks to its neighbours or moves away, and researchers are now mapping their atomic structure to see exactly how they do it. This matters because cells must navigate to the right place during development, wiring the brain, building blood vessels, and maintaining bones. When these guidance systems fail, the consequences include severed nerves that cannot regenerate after spinal cord injury, bone loss in osteoporosis, neurodevelopmental conditions like autism, and the uncontrolled cell movement that drives cancer. Current knowledge of how semaphorins and their receptors (plexins) work together is incomplete, especially at the molecular level where adhesion and motility decisions are actually made. This is fundamental science. The team will use structural biology techniques—producing purified samples, then imaging them at atomic resolution both in isolation and on the cell surface—to reveal the precise mechanical steps that translate an external signal into a change in cell behaviour. If successful, the work will provide a molecular blueprint that pharmaceutical and biotechnology companies can use to design drugs that either block or enhance these guidance signals, potentially opening new routes to treat nerve injury, bone disease, developmental disorders, and cancer.
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The cells of a multicellular organism, such as a human, must be subject to an exquisite choreography during development. Each cell must achieve the particular balance between adhesion and motility appropriate to its role at a specific time and place in the developing organism. Much of the information to direct each cell must be garnered through interaction with its immediate environment including neighbouring cells. These interactions are mediated by various types of receptor molecules embedded in the cell surface. We wish to understand how one family of molecules, the semaphorins, work together with their receptors, the plexins, to control the ability of a cell to stick (adhere) or to move in a specific direction. Using the techniques of structural biology we aim to uncover, in atomic detail, the mechanisms by which the semaphorins and plexins control cell adhesion and guidance, for example in directing the wiring of the brain. These mechanisms must integrate receptor interactions occurring between cells and on the same cell surface, as well as spanning from the extracellular to the intracellular environment. To generate insight into such systems we will need to use state of the art techniques to produce suitable samples of the semaphorins, the plexins and their complexes, and to combine in vitro structural studies on the isolated molecules with in situ analyses in the functionally relevant context of the cell surface. This is basic research into the mechanisms by which biology works to build the nervous system and the blood vessels, to maintain bones and to activate the immune system. By understanding these mechanisms we will also be better equipped to explore molecular factors which may contribute to the failure of severed nerves to regenerate following spinal cord injury, to bone-related disorders, for example osteoporosis, to neurodevelopmental disorders such as autism disorder spectrum, and to cancer. Ultimately this knowledge can be used by the biotechnology and pharmaceutical industries, to inform and guide the design of novel therapeutics.
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