Change in the Molecular Dimension of a RAGE-Ligand Complex Triggers RAGE Signaling

The weak oligomerization exhibited by many transmembrane receptors has a profound effect on signal transduction. The phenomenon is difficult to characterize structurally due to the large sizes of and transient interactions between monomers. The receptor for advanced glycation end products (RAGE), a signaling molecule central to the induction and perpetuation of inflammatory responses, is a weak constitutive oligomer. The RAGE domain interaction surfaces that mediate homo-dimerization were identified by combining segmental isotopic labeling of extracellular soluble RAGE (sRAGE) and nuclear magnetic resonance spectroscopy with chemical cross-linking and mass spectrometry. Molecular modeling suggests that two sRAGE monomers orient head to head forming an asymmetric dimer with the C termini directed toward the cell membrane. Ligand-induced association of RAGE homo-dimers on the cell surface increases the molecular dimension of the receptor, recruiting Diaphanous 1 (DIAPH1) and activating signaling pathways. [Display omitted] •NMR spectroscopy, cross-linking, and MS were used to construct a model of RAGE dimers•Dimers and larger oligomers can form by utilizing the same interacting surfaces•Oligomerization and ligand binding increase the molecular dimension of RAGE•The increase in molecular dimension promotes signal transduction RAGE is a signaling molecule central to the induction and perpetuation of inflammatory responses. The dimerization interaction surfaces on RAGE are identified. Structural modeling suggests that ligand-induced association of dimers on the cell surface increases the molecular dimension of the receptor to recruit Diaphanous 1 and activate signaling pathways.