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PMID:27993971

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Citation

Yu, J, Lee, CY, Changou, CA, Cedano-Prieto, DM, Takada, YK and Takada, Y (2017) The CD9, CD81, and CD151 EC2 domains bind to the classical RGD-binding site of integrin αvβ3. Biochem. J. 474:589-596

Abstract

Tetraspanins play important roles in normal (e.g. cell adhesion, motility, activation, and proliferation) and pathological conditions (e.g. metastasis and viral infection). Tetraspanins interact with integrins and regulate integrin functions, but the specifics of tetraspanin-integrin interactions are unclear. Using co-immunoprecipitation with integrins as a sole method to detect interaction between integrins and full-length tetraspanins, it has been proposed that the variable region (helices D and E) of the extracellular-2 (EC2) domain of tetraspanins laterally associates with a non-ligand-binding site of integrins. We describe that, using adhesion assays, the EC2 domain of CD81, CD9, and CD151 bound to integrin αvβ3, and this binding was suppressed by cRGDfV, a specific inhibitor of αvβ3, and antibody 7E3, which is mapped to the ligand-binding site of β3. We also present evidence that the specificity loop of β3 directly bound to the EC2 domains. This suggests that the EC2 domains specifically bind to the classical ligand-binding site of αvβ3. αvβ3 was a more effective receptor for the EC2 domains than the previously known tetraspanin receptors α3β1, α4β1, and α6β1. Docking simulation predicted that the helices A and B of CD81 EC2 bind to the RGD-binding site of αvβ3. Substituting Lys residues at positions 116 and 144/148 of CD81 EC2 in the predicted integrin-binding interface reduced the binding of CD81 EC2 to αvβ3, consistent with the docking model. These findings suggest that, in contrast with previous models, the ligand-binding site of integrin αvβ3, a new tetraspanin receptor, binds to the constant region (helices A and B) of the EC2 domain.

Links

PubMed Online version:10.1042/BCJ20160998

Keywords

Amino Acid Sequence; Animals; Antibodies, Monoclonal/chemistry; Binding Sites; CHO Cells; Cloning, Molecular; Cricetulus; Escherichia coli/genetics; Escherichia coli/metabolism; Gene Expression; Integrin alphaVbeta3/chemistry; Integrin alphaVbeta3/genetics; Integrin alphaVbeta3/immunology; Kinetics; Molecular Docking Simulation; Protein Binding; Protein Conformation, alpha-Helical; Protein Conformation, beta-Strand; Protein Interaction Domains and Motifs; Recombinant Proteins/chemistry; Recombinant Proteins/genetics; Recombinant Proteins/metabolism; Sequence Alignment; Sequence Homology, Amino Acid; Tetraspanin 24/chemistry; Tetraspanin 24/genetics; Tetraspanin 24/immunology; Tetraspanin 28/chemistry; Tetraspanin 28/genetics; Tetraspanin 28/immunology; Tetraspanin 29/chemistry; Tetraspanin 29/genetics; Tetraspanin 29/immunology

Significance

Annotations

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

HUMAN:CD81

enables

GO:0005178: integrin binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:CD9

enables

GO:0005178: integrin binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:CD151

enables

GO:0005178: integrin binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

Notes

See also

References

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