title: Structure of the repulsive guidance molecule (RGM)-neogenin signaling hub.
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.
authors.affiliation: Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Christian H
authors.initials: CH
authors.lastname: Bell
authors.affiliation: Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Eleanor
authors.initials: E
authors.lastname: Healey
authors.affiliation: Department of Neuroscience and Pharmacology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, CG Utrecht 3584, Netherlands.
authors.forename: Susan
authors.initials: S
authors.lastname: van Erp
authors.affiliation: Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Bishop
authors.affiliation: Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Chenxiang
authors.initials: C
authors.lastname: Tang
authors.affiliation: Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Robert J C
authors.initials: RJC
authors.lastname: Gilbert
authors.affiliation: Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: A Radu
authors.initials: AR
authors.lastname: Aricescu
authors.affiliation: Department of Neuroscience and Pharmacology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, CG Utrecht 3584, Netherlands.
authors.forename: R Jeroen
authors.initials: RJ
authors.lastname: Pasterkamp
authors.affiliation: Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Christian
authors.initials: C
authors.lastname: Siebold
mesh_terms: D000595:Amino Acid Sequence; D055592:Biophysical Phenomena; D015816:Cell Adhesion Molecules, Neuronal / Q000737:chemistry* / Q000235:genetics; D017124:Conserved Sequence; D018360:Crystallography, X-Ray; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry*; D009154:Mutation; D009842:Oligopeptides / Q000737:chemistry; D017434:Protein Structure, Tertiary; D015398:Signal Transduction
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; D008565:Membrane Proteins; D009842:Oligopeptides; C560433:RGMB protein, human; C091279:neogenin; C047981:arginyl-glycyl-aspartic acid