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Cited by 112TGF-β signaling in diseasesAxon Guidance and Neuronal SignalingDevelopmental Biology and Gene Regulation

Repulsive guidance molecule is a structural bridge between neogenin and bone morphogenetic protein

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Healey, Eleanor G, Bishop, Benjamin, Elegheert, Jonathan, Bell, Christian H, Padilla-Parra, Sergi, Siebold, Christian·2015·Nature Structural & Molecular Biology
DOI 10.1038/nsmb.3016PMC PMC4456160
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Abstract

Repulsive guidance molecules (RGMs) control crucial processes including cell motility, adhesion, immune-cell regulation and systemic iron metabolism. RGMs signal via the neogenin (NEO1) and the bone morphogenetic protein (BMP) pathways. Here, we report crystal structures of the N-terminal domains of all human RGM family members in complex with the BMP ligand BMP2, revealing a new protein fold and a conserved BMP-binding mode. Our structural and functional data suggest a pH-linked mechanism for RGM-activated BMP signaling and offer a rationale for RGM mutations causing juvenile hemochromatosis. We also determined the crystal structure of the ternary BMP2-RGM-NEO1 complex, which, along with solution scattering and live-cell super-resolution fluorescence microscopy, indicates BMP-induced clustering of the RGM-NEO1 complex. Our results show how RGM acts as the central hub that links BMP and NEO1 and physically connects these fundamental signaling pathways.

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  • RGM proteins have high affinity for BMPs and can enhance BMP signaling in ways still incompletely understood but involving formation and internalization of a cell surface complex in which RGMb forms a bridge between BMP ligands and Neogenin (Neo).

    “RGM proteins have high affinity for BMPs and can enhance BMP signaling in ways still incompletely understood but involving formation and internalization of a cell surface complex in which RGMb forms a bridge between BMP ligands and Neogenin (Neo) (45, 46).”

    From Agouti and BMP signaling drive a naturally occurring fate conversion of melanophores to leucophores in zebrafish (2025) · cites this paper as [46]

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Cited by

Sorted by citations

Authors
Healey, E. G., Bishop, B., Elegheert, J., Bell, C. H., Padilla-Parra, S., & Siebold, C.
Affiliations
Centre for Human Genetics (GB)
Corresponding author
Siebold, Christian
ORCID
Venue
Nature Structural & Molecular Biology
Publisher
Springer Science and Business Media LLC
Published
2015-05-04
Volume
22
Issue
6
Pages
458-465
ISSN
  • 1545-9985 (ISSN-L)
  • 1545-9993
DOI
10.1038/nsmb.3016
PMC
PMC4456160
OpenAlex
W2170758920
Cited by
112
References
3
Citations by year
2026: 9 · 2025: 10 · 2024: 11 · 2023: 3 · 2022: 12 · 2021: 13 · 2020: 8 · 2019: 7 · 2018: 7 · 2017: 16 · 2016: 12 · 2015: 4
FWCI
5.13
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Structural & Molecular Biology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Wellcome Trust (101584MA, 097301/Z/11/Z, 090532/Z/09/Z)
  • Cancer Research UK (A14414, C20724/A14414, 14414)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Axon Guidance and Neuronal Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
Keywords
repulsive guidance molecules, neogenin, bone morphogenetic proteins, BMP-2, BMP signaling, protein crystal structure, juvenile hemochromatosis, protein clustering, cell motility, cell adhesion
MeSH terms
Humans, Membrane Proteins, Models, Molecular, Protein Binding, Protein Conformation, Cell Adhesion Molecules, Neuronal, Crystallography, X-Ray, Bone Morphogenetic Protein 2, Protein Multimerization

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