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PMID:20877282

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Citation

Janssen, BJ, Robinson, RA, Pérez-Brangulí, F, Bell, CH, Mitchell, KJ, Siebold, C and Jones, EY (2010) Structural basis of semaphorin-plexin signalling. Nature 467:1118-22

Abstract

Cell-cell signalling of semaphorin ligands through interaction with plexin receptors is important for the homeostasis and morphogenesis of many tissues and is widely studied for its role in neural connectivity, cancer, cell migration and immune responses. SEMA4D and Sema6A exemplify two diverse vertebrate, membrane-spanning semaphorin classes (4 and 6) that are capable of direct signalling through members of the two largest plexin classes, B and A, respectively. In the absence of any structural information on the plexin ectodomain or its interaction with semaphorins the extracellular specificity and mechanism controlling plexin signalling has remained unresolved. Here we present crystal structures of cognate complexes of the semaphorin-binding regions of plexins B1 and A2 with semaphorin ectodomains (human PLXNB1(1-2)-SEMA4D(ecto) and murine PlxnA2(1-4)-Sema6A(ecto)), plus unliganded structures of PlxnA2(1-4) and Sema6A(ecto). These structures, together with biophysical and cellular assays of wild-type and mutant proteins, reveal that semaphorin dimers independently bind two plexin molecules and that signalling is critically dependent on the avidity of the resulting bivalent 2:2 complex (monomeric semaphorin binds plexin but fails to trigger signalling). In combination, our data favour a cell-cell signalling mechanism involving semaphorin-stabilized plexin dimerization, possibly followed by clustering, which is consistent with previous functional data. Furthermore, the shared generic architecture of the complexes, formed through conserved contacts of the amino-terminal seven-bladed β-propeller (sema) domains of both semaphorin and plexin, suggests that a common mode of interaction triggers all semaphorin-plexin based signalling, while distinct insertions within or between blades of the sema domains determine binding specificity.

Links

PubMed Online version:10.1038/nature09468

Keywords

Animals; Antigens, CD/chemistry; Antigens, CD/genetics; Antigens, CD/metabolism; Binding Sites; Cell Adhesion Molecules/chemistry; Cell Adhesion Molecules/genetics; Cell Adhesion Molecules/metabolism; Cell Communication; Crystallography, X-Ray; Humans; Ligands; Mice; Mice, Inbred C57BL; Models, Molecular; NIH 3T3 Cells; Nerve Tissue Proteins/chemistry; Nerve Tissue Proteins/genetics; Nerve Tissue Proteins/metabolism; Protein Binding; Protein Structure, Tertiary; Receptors, Cell Surface/chemistry; Receptors, Cell Surface/genetics; Receptors, Cell Surface/metabolism; Semaphorins/chemistry; Semaphorins/genetics; Semaphorins/metabolism; Signal Transduction; Structure-Activity Relationship

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:SEM6A

part_of

GO:0005887: integral component of plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:SEM6A

involved_in

GO:2001224: positive regulation of neuron migration

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SEM6A

enables

GO:0004888: transmembrane signaling receptor activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:SEM6A

involved_in

GO:0071526: semaphorin-plexin signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SEM6A

enables

GO:0042802: identical protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O35464-1

F

Seeded From UniProt

complete

MOUSE:SEM6A

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P70207

F

Seeded From UniProt

complete

HUMAN:PLXB1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q92854

F

Seeded From UniProt

complete

HUMAN:PLXB1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q92854-1

F

Seeded From UniProt

complete

MOUSE:PLXA2

involved_in

GO:0030334: regulation of cell migration

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PLXA2

involved_in

GO:0071526: semaphorin-plexin signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PLXA2

enables

GO:0017154: semaphorin receptor activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:PLXA2

enables

GO:0042802: identical protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P70207

F

Seeded From UniProt

complete

MOUSE:PLXA2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O35464-1

F

Seeded From UniProt

complete

HUMAN:SEM4D

enables

GO:0004888: transmembrane signaling receptor activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:SEM4D

enables

GO:0005102: signaling receptor binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:SEM4D

involved_in

GO:0008360: regulation of cell shape

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SEM4D

involved_in

GO:0071526: semaphorin-plexin signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SEM4D

involved_in

GO:0031344: regulation of cell projection organization

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SEM4D

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O43157

F

Seeded From UniProt

complete

HUMAN:PLXB1

enables

GO:0042802: identical protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q92854-1

F

Seeded From UniProt

complete

HUMAN:PLXB1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O43157-1

F

Seeded From UniProt

complete


See also

References

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