Repulsive guidance molecule is a structural bridge between neogenin and bone morphogenetic protein.
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.
Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Eleanor G
EG
Healey
Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Benjamin
B
Bishop
Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Jonathan
J
Elegheert
Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Christian H
CH
Bell
1] Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. [2] Cellular Imaging Core, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Sergi
S
Padilla-Parra
Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Christian
C
Siebold
D055396:Bone Morphogenetic Protein 2 / Q000737:chemistry* / Q000378:metabolism; D015816:Cell Adhesion Molecules, Neuronal / Q000737:chemistry* / Q000378:metabolism; D018360:Crystallography, X-Ray; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D055503:Protein Multimerization
C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; D015816:Cell Adhesion Molecules, Neuronal; D008565:Membrane Proteins; C091279:neogenin