西亚试剂：Cytoplasmic Relaxation of Active Eph Controls Ephrin Sheddi

Cytoplasmic Relaxation of Active Eph Controls Ephrin Shedding by ADAM10

Peter W. Janes1#, Sabine H. Wimmer-Kleikamp1,2,3#¤, Achilleas S. Frangakis2, Kane Treble1, Bettina Griesshaber1, Ola Sabet3, Markus Grabenbauer3, Alice Y. Ting4, Paul Saftig5, Philippe I. Bastiaens2,3*, Martin Lackmann1*

1 Department of Biochemistry and Molecular Biology, Monash University, Victoria, Australia, 2 European Molecular Biology Laboratory, Heidelberg, Germany, 3 Department of Systemic Cell Biology, Max Planck Institute of Molecular Physiology, Dortmund, Germany, 4 Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America, 5 Biochemical Institute, Christian-Albrecht-University, Kiel, Germany

Release of cell surface-bound ligands by A-Disintegrin-And-Metalloprotease (ADAM) transmembrane metalloproteases is essential for signalling by cytokine, cell adhesion, and tyrosine kinase receptors. For Eph receptor ligands, it provides the switch between cell-cell adhesion and repulsion. Ligand shedding is tightly controlled by intrinsic tyrosine kinase activity, which for Eph receptors relies on the release of an inhibitory interaction of the cytoplasmic juxtamembrane segment with the kinase domain. However, a mechanism linking kinase and sheddase activities had remained elusive. We demonstrate that it is a membrane-proximal localisation of the latent kinase domain that prevents ephrin ligand shedding in trans. Fluorescence lifetime imaging microscopy and electron tomography reveal that activation extends the Eph receptor tyrosine kinase intracellular domain away from the cell membrane into a conformation that facilitates productive association with ADAM10. Accordingly, EphA3 mutants with constitutively-released kinase domains efficiently support shedding, even when their kinase is disabled. Our data suggest that this phosphorylation-activated conformational switch of EphA3 directly controls ADAM-mediated shedding.

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