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

DOI: 10.1038/nsmb.3016 DOI Help
PMID: 25938661 PMID Help

Authors: Eleanor Healey (Wellcome Trust Centre for Human Genetics, University of Oxford) , Benjamin Bishop (Wellcome Trust Centre for Human Genetics, University of Oxford) , Jonathan Elegheert (Wellcome Trust Centre for Human Genetics, University of Oxford) , Christian Bell (Wellcome Trust Centre for Human Genetics, University of Oxford) , Sergi Padilla-Parra (Wellcome Trust Centre for Human Genetics, University of Oxford) , Christian Siebold (Wellcome Trust Centre for Human Genetics, University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Structural & Molecular Biology , VOL 22 (6) , PAGES 458 - 465

State: Published (Approved)
Published: May 2015
Diamond Proposal Number(s): 10627

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.

Journal Keywords: Cell signalling; Developmental biology; Diseases

Subject Areas: Biology and Bio-materials


Instruments: I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography

Other Facilities: BM29 at the European Synchrotron Radiation Facility (SAXS data)

Added On: 23/09/2015 12:08

Discipline Tags:

Health & Wellbeing Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)