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

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...

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Published inScience (American Association for the Advancement of Science) Vol. 341; no. 6141; pp. 77 - 80
Main Authors Bell, Christian H., Healey, Eleanor, van Erp, Susan, Bishop, Benjamin, Tang, Chenxiang, Gilbert, Robert J.C., Aricescu, A. Radu, Pasterkamp, R. Jeroen, Siebold, Christian
Format Journal Article
LanguageEnglish
Published United States American Association for the Advancement of Science 05.07.2013
The American Association for the Advancement of Science
Subjects
Amino Acid Sequence
Biophysical Phenomena
Cell Adhesion Molecules, Neuronal - chemistry
Cell Adhesion Molecules, Neuronal - genetics
Cellular biology
Cleavage
Conserved Sequence
Crystal structure
Crystallography, X-Ray
Crystals
Dimers
Family members
Guidance
Humans
Ligands
Membrane Proteins - chemistry
Molecular structure
Molecules
Mutagenesis
Mutation
Neurites
Neurons
Oligopeptides - chemistry
Protein Structure, Tertiary
Proteins
Proteomics
Receptors
Secretions
Signal Transduction
Stoichiometry
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Summary: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.
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Present address: Molecular Biophysics and Biochemistry Department, Yale University, 260 Whitney Avenue, New Haven, CT 06520–8114, USA.
Present address: Roche Diagnostics GmbH, Nonnenwald 2, 82377 Penzberg, Germany.
ISSN:0036-8075
1095-9203
DOI:10.1126/science.1232322