Abstract
The Receptor for Advanced Glycation End-products (RAGE) is a pattern recognition receptor from the immunoglobulin superfamily. It recognizes a broad spectrum of endogenous, danger-associated patterns present in the extracellular compartment. Despite their divergence in nature and tissue localization, a hallmark of RAGE ligands is their accumulation in diseased tissues at early stages of the pathology development. Thus, increased levels of AGEs are encountered in diabetes and renal insufficiency, amyloid fibrils accumulation in the brain is characteristic of Alzheimer's disease, HMGB1 protein is secreted by cells during inflammation, and S100 proteins accumulate in the environment of tumors. Ligand binding to RAGE ectodomain activates downstream signaling cascades which in turn trigger NFkB and other transcription factors activation, allowing the overexpression of pro-inflammatory molecules. Ligand accumulation therefore acts as a propagation factor of the cellular dysfunction through extensive RAGE-mediated cell activation. This maintains a high inflammatory state which imposes a massive stress on the cells, ultimately leading to tissue damage rather than healing and recovery. RAGE blockade has therefore been considered as a promising therapeutical strategy in various pathological settings. However, after a decade of efforts put in that direction, the results are still unclear, probably due to the fact that RAGE-mediated signaling has also a protective effect in tissue homeostasis and resolution of inflammation. To determine the structural basis for RAGE signaling and to be able to design specific, efficient modulators of the receptor, we have pursued the structure determination of several RAGE:ligand complexes. As a first result, we have obtained the crystal structure of the complex between the human RAGE ectodomain and the mouse S100A6 protein at 2.3 Å resolution. This structure reveals how ligand binding can induce a novel dimeric conformation of RAGE, that appears to be suited for signal transduction and effector binding to the intracellular domain of the receptor. Surprisingly, the structure reveals a new, unexpected conformation for the dimeric S100A6 ligand. Modeling and bioinformatics suggest that this might be a common feature for several other S100 proteins upon binding to RAGE. This S100 conformation might therefore constitute a promising target for drug design of specific inhibitors with therapeutical potential for treating e.g. cancer and neurodegenerative diseases.