Adam meets Eph: An ADAM substrate recognition module acts as a molecular switch for ephrin cleavage in trans Journal Article
| Authors: | Janes, P. W.; Saha, N.; Barton, W. A.; Kolev, M. V.; Wimmer-Kleikamp, S. H.; Nievergall, E.; Blobel, C. P.; Himanen, J. P.; Lackmann, M.; Nikolov, D. B. |
| Article Title: | Adam meets Eph: An ADAM substrate recognition module acts as a molecular switch for ephrin cleavage in trans |
| Abstract: | The Eph family of receptor tyrosine kinases and their ephrin ligands are mediators of cell-cell communication. Cleavage of ephrin-A2 by the ADAM10 membrane metalloprotease enables contact repulsion between Eph- and ephrin-expressing cells. How ADAM10 interacts with ephrins in a regulated manner to cleave only Eph bound ephrin molecules remains unclear. The structure of ADAM10 disintegrin and cysteine-rich domains and the functional studies presented here define an essential substrate-recognition module for functional interaction of ADAM10 with the ephrin-A5/EphA3 complex. While ADAM10 constitutively associates with EphA3, the formation of a functional EphA3/ephrin-A5 complex creates a new molecular recognition motif for the ADAM10 cysteine-rich domain that positions the proteinase domain for effective ephrin-A5 cleavage. Surprisingly, the cleavage occurs in trans, with ADAM10 and its substrate being on the membranes of opposing cells. Our data suggest a simple mechanism for regulating ADAM10-mediated ephrin proteolysis, which ensures that only Eph bound ephrins are recognized and cleaved. Copyright ©2005 by Elsevier Inc. |
| Keywords: | controlled study; unclassified drug; human cell; protein domain; protein motif; microscopy, confocal; embryo; protein degradation; protein protein interaction; cell line; membrane proteins; rna, small interfering; rna interference; enzyme substrate; cell line, tumor; blotting, western; amino acid sequence; conserved sequence; molecular sequence data; sequence homology, amino acid; substrate specificity; ligands; green fluorescent proteins; models, molecular; crystallography, x-ray; protein structure, tertiary; protein folding; enzyme structure; hydrolysis; protein structure, secondary; mutagenesis; ephrin-a2; disulfides; cysteine; metalloproteinase; adam proteins; amyloid precursor protein secretases; phylogeny; ephrin-a5; ephrin a5; receptor, epha3; a disintegrin and metalloprotease 10; ephrin-a3; precipitin tests |
| Journal Title: | Cell |
| Volume: | 123 |
| Issue: | 2 |
| ISSN: | 0092-8674 |
| Publisher: | Cell Press |
| Date Published: | 2005-10-21 |
| Start Page: | 291 |
| End Page: | 304 |
| Language: | English |
| DOI: | 10.1016/j.cell.2005.08.014 |
| PUBMED: | 16239146 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 165" - "Export Date: 24 October 2012" - "CODEN: CELLB" - "Source: Scopus" |
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