Structure of the Repulsive Guidance Molecule (RGM)–Neogenin Signaling Hub

Christian H. Bell, Eleanor Healey, Susan van Erp, Benjamin Bishop, Chenxiang Tang, Robert J. C. Gilbert, A. Radu Aricescu, R. Jeroen Pasterkamp, Christian Siebold*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Repulsive guidance molecule family members (RGMs) control fundamental and diverse cellular processes, including motility and adhesion, immune cell regulation, and systemic iron metabolism. However, it is not known how RGMs initiate signaling through their common cell-surface receptor, neogenin (NEO1). Here, we present crystal structures of the NEO1 RGM-binding region and its complex with human RGMB (also called dragon). The RGMB structure reveals a previously unknown protein fold and a functionally important autocatalytic cleavage mechanism and provides a framework to explain numerous disease-linked mutations in RGMs. In the complex, two RGMB ectodomains conformationally stabilize the juxtamembrane regions of two NEO1 receptors in a pH-dependent manner. We demonstrate that all RGM-NEO1 complexes share this architecture, which therefore represents the core of multiple signaling pathways.
Original languageEnglish
Pages (from-to)77-80
Number of pages4
JournalScience
Volume341
Issue number6141
DOIs
Publication statusPublished - 5 Jul 2013

Keywords

  • Amino Acid Sequence
  • Biophysical Phenomena
  • Cell Adhesion Molecules, Neuronal
  • Conserved Sequence
  • Crystallography, X-Ray
  • Humans
  • Membrane Proteins
  • Mutation
  • Oligopeptides
  • Protein Structure, Tertiary
  • Signal Transduction

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