Adam meets Eph: an ADAM substrate recognition module acts as a molecular switch for ephrin cleavage in trans.
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.
Janes
Peter W
PW
Department of Biochemistry and Molecular Biology, PO Box 13D, Monash University, Victoria 3800, Australia.
Saha
Nayanendu
N
Barton
William A
WA
Kolev
Momchil V
MV
Wimmer-Kleikamp
Sabine H
SH
Nievergall
Eva
E
Blobel
Carl P
CP
Himanen
Juha-Pekka
JP
Lackmann
Martin
M
Nikolov
Dimitar B
DB
D051722:ADAM Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000072197:ADAM10 Protein; D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D017124:Conserved Sequence; D018360:Crystallography, X-Ray; D003545:Cysteine / Q000737:chemistry; D004220:Disulfides / Q000737:chemistry; D036383:Ephrin-A2 / Q000378:metabolism*; D036384:Ephrin-A3 / Q000737:chemistry / Q000378:metabolism*; D036386:Ephrin-A5 / Q000737:chemistry / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D008024:Ligands; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018613:Microscopy, Confocal; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016296:Mutagenesis; D010802:Phylogeny; D011233:Precipitin Tests; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D036121:Receptor, EphA3 / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013379:Substrate Specificity
D004220:Disulfides; D036383:Ephrin-A2; D036384:Ephrin-A3; D036386:Ephrin-A5; D008024:Ligands; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D049452:Green Fluorescent Proteins; D036121:Receptor, EphA3; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human; D003545:Cysteine