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Understanding cell signalling systems: paving the way for new therapies.

Jones EY - Philos Trans A Math Phys Eng Sci (2015)

Bottom Line: Importantly, we can complement protein crystallographic results with biophysical and cellular studies to dovetail structural information with functional impact.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.

View Article: PubMed Central - PubMed

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.

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.

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Related in: MedlinePlus

Drawing of Purkinje cells (A) and granule cells (B) from pigeon cerebellum. Credit: Santiago Ramón y Cajal, 1899. Instituto Santiago Ramón y Cajal, Madrid, Spain. (Online version in colour.)
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RSTA20130155F1: Drawing of Purkinje cells (A) and granule cells (B) from pigeon cerebellum. Credit: Santiago Ramón y Cajal, 1899. Instituto Santiago Ramón y Cajal, Madrid, Spain. (Online version in colour.)

Mentions: The Instituto Santiago Ramón y Cajal in Madrid has in its keeping a seminal series of ink drawings made towards the end of the nineteenth century. In these drawings, Cajal records observations he made using the cutting-edge microscopy techniques of his day. The drawings show the intricate networks formed by the dendrites and axons extending from cells of the nervous system in, for example, a pigeon cerebellum (figure 1). The complexity of this cellular organization led Cajal to the hypothesis that this organization must be the result of guidance mechanisms provided by chemical gradients. A century later, in the 1990s, four families of protein molecules were characterized as the providers of guidance cues during neuronal development: the netrins, slits, ephrins and semaphorins [1]. The wiring of nervous systems, ranging from fly to human, requires cell surface receptor-based signalling systems to guide the growing neurites to their correct locations. Indeed, it is now apparent that the development and homeostasis of tissues throughout the human body is founded on cell guidance systems. The common theme running through the mechanisms of action of these systems is that binding of the extracellular ligand, a secreted or cell attached guidance cue, to a cell surface receptor triggers intracellular signals which cause localized changes in the cytoskeleton. This review focuses on recent insights into the atomic-level workings of the semaphorin system of guidance cues; results, over 100 years after Santiago Ramón y Cajal, of the cutting-edge technology of today at the Diamond Light Source.Figure 1.


Understanding cell signalling systems: paving the way for new therapies.

Jones EY - Philos Trans A Math Phys Eng Sci (2015)

Drawing of Purkinje cells (A) and granule cells (B) from pigeon cerebellum. Credit: Santiago Ramón y Cajal, 1899. Instituto Santiago Ramón y Cajal, Madrid, Spain. (Online version in colour.)
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4308982&req=5

RSTA20130155F1: Drawing of Purkinje cells (A) and granule cells (B) from pigeon cerebellum. Credit: Santiago Ramón y Cajal, 1899. Instituto Santiago Ramón y Cajal, Madrid, Spain. (Online version in colour.)
Mentions: The Instituto Santiago Ramón y Cajal in Madrid has in its keeping a seminal series of ink drawings made towards the end of the nineteenth century. In these drawings, Cajal records observations he made using the cutting-edge microscopy techniques of his day. The drawings show the intricate networks formed by the dendrites and axons extending from cells of the nervous system in, for example, a pigeon cerebellum (figure 1). The complexity of this cellular organization led Cajal to the hypothesis that this organization must be the result of guidance mechanisms provided by chemical gradients. A century later, in the 1990s, four families of protein molecules were characterized as the providers of guidance cues during neuronal development: the netrins, slits, ephrins and semaphorins [1]. The wiring of nervous systems, ranging from fly to human, requires cell surface receptor-based signalling systems to guide the growing neurites to their correct locations. Indeed, it is now apparent that the development and homeostasis of tissues throughout the human body is founded on cell guidance systems. The common theme running through the mechanisms of action of these systems is that binding of the extracellular ligand, a secreted or cell attached guidance cue, to a cell surface receptor triggers intracellular signals which cause localized changes in the cytoskeleton. This review focuses on recent insights into the atomic-level workings of the semaphorin system of guidance cues; results, over 100 years after Santiago Ramón y Cajal, of the cutting-edge technology of today at the Diamond Light Source.Figure 1.

Bottom Line: Importantly, we can complement protein crystallographic results with biophysical and cellular studies to dovetail structural information with functional impact.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.

View Article: PubMed Central - PubMed

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.

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.

Show MeSH
Related in: MedlinePlus