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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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Ribbon representations of semaphorin, plexin and semaphorin–plexin complex structures. (a) mSema6Aecto (sema domain in blue and PSI domain in cyan). (b) mPlxnA21−4 (sema domain in red, first PSI domain in pink, Ig-like IPT domain in wheat and second PSI domain in crimson). (c) The mPlxnA21−4–mSema6Aecto complex (colours as in previous panels). The second (C terminal) PSI domain is included in the unliganded mPlxnA21−4 crystal structure but lacks well-ordered electron density in the complex crystal structure.
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RSTA20130155F2: Ribbon representations of semaphorin, plexin and semaphorin–plexin complex structures. (a) mSema6Aecto (sema domain in blue and PSI domain in cyan). (b) mPlxnA21−4 (sema domain in red, first PSI domain in pink, Ig-like IPT domain in wheat and second PSI domain in crimson). (c) The mPlxnA21−4–mSema6Aecto complex (colours as in previous panels). The second (C terminal) PSI domain is included in the unliganded mPlxnA21−4 crystal structure but lacks well-ordered electron density in the complex crystal structure.

Mentions: In 2003, my laboratory (in Oxford) and that of Prof. Dimitar Nikolov (at the Sloan Kettering Institute, New York) contemporaneously determined crystal structures of the semaphorin sema domain [10,11], the hallmark N-terminal domain implicated in plexin recognition. The vertebrate semaphorins are grouped, based on ectodomain sequence, into the secreted class 3 semaphorins (the Sema3s), and the cell attached (by single transmembrane helix or GPI anchor) semaphorin classes 4, 5, 6 and 7. Our crystal structure of the human Sema4D ectodomain (hSema4Decto) [10] revealed a seven-bladed β-propeller (the sema domain), a cysteine-rich knot (the PSI domain) and an Ig-like β-sandwich domain. The β-propeller topology, commonly found in extracellular and cytosolic proteins, comprises a series of four-strand anti-parallel β-sheets (the blades) arrayed sequentially around a central axis and locked into full circle by an N-terminal β-strand providing the outermost component of the C-terminal blade (figure 2a). The sema domain β-propeller topology is distinguished by an elaborate insertion (of some 70 residues between β-strands C and D of blade 5) that we termed the extrusion [10]. The first crystal structures also revealed the homodimeric architecture of the semaphorins [10,11]. The key factor mediating the dimerization is the sema domain; the top surfaces of the β-propellers abut, off-centre, to form a ‘face-to-face’ interface (figure 2a). In total, there are now crystal structures for class 3, 4, 6 and 7 semaphorins [10–15]. All show the same dimeric architecture, posing the question how might this property of the sema domain contribute to function?Figure 2.


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

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

Ribbon representations of semaphorin, plexin and semaphorin–plexin complex structures. (a) mSema6Aecto (sema domain in blue and PSI domain in cyan). (b) mPlxnA21−4 (sema domain in red, first PSI domain in pink, Ig-like IPT domain in wheat and second PSI domain in crimson). (c) The mPlxnA21−4–mSema6Aecto complex (colours as in previous panels). The second (C terminal) PSI domain is included in the unliganded mPlxnA21−4 crystal structure but lacks well-ordered electron density in the complex crystal structure.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

RSTA20130155F2: Ribbon representations of semaphorin, plexin and semaphorin–plexin complex structures. (a) mSema6Aecto (sema domain in blue and PSI domain in cyan). (b) mPlxnA21−4 (sema domain in red, first PSI domain in pink, Ig-like IPT domain in wheat and second PSI domain in crimson). (c) The mPlxnA21−4–mSema6Aecto complex (colours as in previous panels). The second (C terminal) PSI domain is included in the unliganded mPlxnA21−4 crystal structure but lacks well-ordered electron density in the complex crystal structure.
Mentions: In 2003, my laboratory (in Oxford) and that of Prof. Dimitar Nikolov (at the Sloan Kettering Institute, New York) contemporaneously determined crystal structures of the semaphorin sema domain [10,11], the hallmark N-terminal domain implicated in plexin recognition. The vertebrate semaphorins are grouped, based on ectodomain sequence, into the secreted class 3 semaphorins (the Sema3s), and the cell attached (by single transmembrane helix or GPI anchor) semaphorin classes 4, 5, 6 and 7. Our crystal structure of the human Sema4D ectodomain (hSema4Decto) [10] revealed a seven-bladed β-propeller (the sema domain), a cysteine-rich knot (the PSI domain) and an Ig-like β-sandwich domain. The β-propeller topology, commonly found in extracellular and cytosolic proteins, comprises a series of four-strand anti-parallel β-sheets (the blades) arrayed sequentially around a central axis and locked into full circle by an N-terminal β-strand providing the outermost component of the C-terminal blade (figure 2a). The sema domain β-propeller topology is distinguished by an elaborate insertion (of some 70 residues between β-strands C and D of blade 5) that we termed the extrusion [10]. The first crystal structures also revealed the homodimeric architecture of the semaphorins [10,11]. The key factor mediating the dimerization is the sema domain; the top surfaces of the β-propellers abut, off-centre, to form a ‘face-to-face’ interface (figure 2a). In total, there are now crystal structures for class 3, 4, 6 and 7 semaphorins [10–15]. All show the same dimeric architecture, posing the question how might this property of the sema domain contribute to function?Figure 2.

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