Repulsive guidance molecule is a structural bridge between neogenin and bone morphogenetic protein.
Nat Struct Mol Biol. 2015-05-04; 22(6): 458-465
DOI: 10.1038/nsmb.3016
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1. Nat Struct Mol Biol. 2015 Jun;22(6):458-65. doi: 10.1038/nsmb.3016. Epub 2015 May
4.
Repulsive guidance molecule is a structural bridge between neogenin and bone
morphogenetic protein.
Healey EG(1), Bishop B(1), Elegheert J(1), Bell CH(1), Padilla-Parra S(2),
Siebold C(1).
Author information:
(1)Division of Structural Biology, Wellcome Trust Centre for Human Genetics,
University of Oxford, Oxford, UK.
(2)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.
Comment in
Nat Struct Mol Biol. 2015 Jun;22(6):439-40.
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.
DOI: 10.1038/nsmb.3016
PMCID: PMC4456160
PMID: 25938661 [Indexed for MEDLINE]