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

Nat Struct Mol Biol. 2015 Jun;22(6):458-65. doi: 10.1038/nsmb.3016. Epub 2015 May 4.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bone Morphogenetic Protein 2 / chemistry*
  • Bone Morphogenetic Protein 2 / metabolism
  • Cell Adhesion Molecules, Neuronal / chemistry*
  • Cell Adhesion Molecules, Neuronal / metabolism
  • Crystallography, X-Ray
  • Humans
  • Membrane Proteins / chemistry*
  • Membrane Proteins / metabolism
  • Models, Molecular
  • Protein Binding
  • Protein Conformation
  • Protein Multimerization*


  • BMP2 protein, human
  • Bone Morphogenetic Protein 2
  • Cell Adhesion Molecules, Neuronal
  • Membrane Proteins
  • neogenin

Associated data

  • PDB/4UHY
  • PDB/4UHZ
  • PDB/4UI0
  • PDB/4UI1
  • PDB/4UI2