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Structure of the repulsive guidance molecule (RGM)-neogenin signaling hub.

TitleStructure of the repulsive guidance molecule (RGM)-neogenin signaling hub.
Publication TypeJournal Article
Year of Publication2013
AuthorsBell CH, Healey E, van Erp S, Bishop B, Tang C, Gilbert RJC, A Aricescu R, R Pasterkamp J, Siebold C
Date Published2013 Jul 5
KeywordsAmino Acid Sequence, Biophysical Phenomena, Cell Adhesion Molecules, Neuronal, Conserved Sequence, Crystallography, X-Ray, Humans, Membrane Proteins, Mutation, Oligopeptides, Protein Structure, Tertiary, Signal Transduction

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.

Alternate JournalScience
PubMed ID23744777
Grant List090532 / / Wellcome Trust / United Kingdom
14414 / / Cancer Research UK / United Kingdom
G0700232 / / Medical Research Council / United Kingdom
/ / Medical Research Council / United Kingdom
/ / Wellcome Trust / United Kingdom
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