Adam meets Eph: an ADAM substrate recognition module acts as a molecular switch for ephrin cleavage in trans

Cell. 2005 Oct 21;123(2):291-304. doi: 10.1016/j.cell.2005.08.014.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • ADAM Proteins / chemistry
  • ADAM Proteins / genetics
  • ADAM Proteins / metabolism*
  • ADAM10 Protein
  • Amino Acid Sequence
  • Amyloid Precursor Protein Secretases
  • Blotting, Western
  • Cell Line
  • Cell Line, Tumor
  • Conserved Sequence
  • Crystallography, X-Ray
  • Cysteine / chemistry
  • Disulfides / chemistry
  • Ephrin-A2 / metabolism*
  • Ephrin-A3 / chemistry
  • Ephrin-A3 / metabolism*
  • Ephrin-A5 / chemistry
  • Ephrin-A5 / metabolism*
  • Green Fluorescent Proteins / metabolism
  • Humans
  • Hydrolysis
  • Ligands
  • Membrane Proteins / chemistry
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Microscopy, Confocal
  • Models, Molecular
  • Molecular Sequence Data
  • Mutagenesis
  • Phylogeny
  • Precipitin Tests
  • Protein Folding
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Receptor, EphA3 / metabolism
  • Sequence Homology, Amino Acid
  • Substrate Specificity


  • Disulfides
  • Ephrin-A2
  • Ephrin-A3
  • Ephrin-A5
  • Ligands
  • Membrane Proteins
  • RNA, Small Interfering
  • Green Fluorescent Proteins
  • Receptor, EphA3
  • Amyloid Precursor Protein Secretases
  • ADAM Proteins
  • ADAM10 Protein
  • ADAM10 protein, human
  • Cysteine

Associated data

  • PDB/2AO7