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

Abstract

Summary The weak oligomerization exhibited by many transmembrane receptors has a profound effect on signal transduction. The phenomenon is difficult to structurally characterize 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 NMR spectroscopy with chemical crosslinking and mass spectrometry. Molecular modeling suggests that two sRAGE monomers orient head-to-head forming an asymmetric dimer with the C-termini directed towards 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.

Receptor for Advanced Glycation End Products (RAGE) and Mechanisms and Therapeutic Opportunities in Diabetes and Cardiovascular Disease: Insights From Human Subjects and Animal Models

“…These ligands bind to the extracellular domains of RAGE in a heterogeneous manner; although the extracellular V-type immunoglobulin (Ig) domain binds to many of the ligand families, the binding sites on the V-domain are multiple and spatially distinct. Further, ligands may also bind at the extracellular C1 and C2-type Ig domains, thereby further diversifying the complexity of the RAGE-ligand interactions (11)(12)(13)(14).…”

2016 ATVB Plenary Lecture

“…Recent experiments by Shekhtman and colleagues illustrated that RAGE forms constitutive homo-dimers through its extracellular VC1 and C2 domains and that upon ligand engagement, the molecular dimension of RAGE increases, thereby allowing its cytoplasmic domain to recruit DIAPH1 and to initiate signaling 50 . In that work, mutations of DIAPH1 were prepared, which indicated that full-length DIAPH1 is required for RAGE signal transduction stimulated by RAGE ligands such as S100B.…”

The receptor for advanced glycation end products (RAGE) and DIAPH1: unique mechanisms and healing the wounded vascular system

“…In addition to the study of the biological implications of RAGE and DIAPH1 in diabetes-and vascular disease-associated disease models, extensive efforts have unveiled the nature of the interaction of the cytoplasmic domain of RAGE with the FH1 (formin homology domain 1) of DIAPH1. Shekhtman's laboratory has shown that the amino acid residues R5 and Q6 in the RAGE cytoplasmic domain are required for the interaction with DIAPH1 and that the induction of the association of RAGE homo-dimers on the cell surface by RAGE ligands increases the molecular dimension of RAGE, thereby recruiting DIAPH1 and, consequently, triggering the activation of signal transduction pathways [22,23].…”