Repulsive guidance molecules lock growth differentiation factor 5 in an inhibitory complex
Tomas Malinauskas1, Tina V Peer2, Benjamin Bishop3
1Division of Structural Biology, Wellcome Centre for Human Genetics, University of Oxford, OX3 7BN Oxford, United Kingdom; tomas@strubi.ox.ac.uk mueller@biozentrum.uni-wuerzburg.de christian@strubi.ox.ac.uk.
Summary
Repulsive guidance molecules (RGMs) surprisingly inhibit GDF5 signaling, unlike their known enhancement of BMP2. RGMs act as a switch, altering signaling pathways through complex interactions with receptors and ligands.
Area of Science:
- Molecular Biology
- Cell Signaling
- Structural Biology
Background:
- Repulsive guidance molecules (RGMs) are cell surface proteins crucial for tissue development and homeostasis.
- RGMs interact with Neogenin (NEO1) and coreceptor for bone morphogenetic protein (BMP)/growth differentiation factor (GDF) family ligands.
Purpose of the Study:
- To determine the structural basis of RGM interactions with GDF5 and NEO1.
- To elucidate the mechanism by which RGMs regulate GDF5 signaling.
Main Methods:
- Crystal structure determination of RGM-GDF5 and NEO1-RGMB-GDF5 complexes.
- Structure-guided mutagenesis of RGMs and BMP ligands.
- In vitro binding studies and cellular assays.
Main Results:
- All three human RGMs inhibit GDF5 signaling, contrasting with their known enhancement of BMP2 signaling.
- RGMs bind to the BMP type 1 receptor site, similar to RGM-BMP2 complexes.
- RGMB bridges NEO1 and GDF5, indicating cross-talk between GDF5 and NEO1 pathways.
- A complex mechanism, not simple competition, underlies RGM-mediated GDF5 inhibition.
Conclusions:
- RGMs act as functionality-switching regulators for GDF5 signaling.
- The findings reveal a novel inhibitory role for RGMs in GDF5 pathways.
- Structural insights explain the distinct regulatory roles of RGMs on different BMP/GDF ligands.
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