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

Area of Science:

• Molecular biology
• Structural biology
• Cell signaling

Background:

• Repulsive guidance molecules (RGMs) are key regulators of cell motility, adhesion, immune responses, and iron metabolism.
• RGMs mediate cellular functions through interactions with neogenin (NEO1) and bone morphogenetic protein (BMP) signaling pathways.

Purpose of the Study:

• To elucidate the structural basis of RGM-BMP interactions and the mechanism of RGM-mediated signaling.
• To investigate the role of RGMs in connecting BMP and NEO1 pathways.

Main Methods:

• X-ray crystallography to determine the structures of RGM-BMP and RGM-NEO1 complexes.
• Biochemical assays and functional studies to analyze RGM signaling.
• Solution scattering and super-resolution fluorescence microscopy to study complex formation in cells.

Main Results:

• Determined crystal structures of human RGM N-terminal domains with BMP2, revealing a novel protein fold and conserved binding mode.
• Identified a pH-dependent mechanism for RGM-activated BMP signaling.
• Structural and microscopy data show BMP-induced clustering of the RGM-NEO1 complex, with RGMs acting as a central hub linking BMP and NEO1 pathways.

Conclusions:

• RGMs serve as a crucial molecular hub, integrating BMP and NEO1 signaling pathways.
• The findings provide insights into the molecular mechanisms underlying RGM function and potential links to diseases like juvenile hemochromatosis.