4IM8

low resolution crystal structure of mouse RAGE

4IM8 の概要

• エントリーDOI: 10.2210/pdb4im8/pdb
• 分子名称: Advanced glycation end-products receptor (1 entity in total)
• 機能のキーワード: heparan sulfate, signaling protein
• 由来する生物種: Mus musculus (mouse)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 22926.32

構造登録者

Xu, D.,Young, J.H.,Krahn, J.M.,Song, D.,Corbett, K.D.,Chazin, W.J.,Pedersen, L.C.,Esko, J.D. (登録日: 2013-01-02, 公開日: 2013-08-14, 最終更新日: 2024-11-20)

主引用文献

Xu, D.,Young, J.H.,Krahn, J.M.,Song, D.,Corbett, K.D.,Chazin, W.J.,Pedersen, L.C.,Esko, J.D.
Stable RAGE-Heparan Sulfate Complexes Are Essential for Signal Transduction.
Acs Chem.Biol., 8:1611-1620, 2013

PubMed Abstract: RAGE (Receptor for Advanced Glycation End-Products) has emerged as a major receptor that mediates vascular inflammation. Signaling through RAGE by damage-associated molecular pattern molecules often leads to uncontrolled inflammation that exacerbates the impact of the underlying disease. Oligomerization of RAGE is believed to play an essential role in signal transduction, but the molecular mechanism of oligomerization remains elusive. Here we report that RAGE activation of Erk1/2 phosphorylation on endothelial cells in response to a number of ligands depends on a mechanism that involves heparan sulfate-induced hexamerization of the RAGE extracellular domain. Structural studies of the extracellular V-C1 domain-dodecasaccharide complex by X-ray diffraction and small-angle X-ray scattering revealed that the hexamer consists of a trimer of dimers, with a stoichiometry of 2:1 RAGE:dodecasaccharide. Mutagenesis studies mapped the heparan sulfate binding site and the interfacial surface between the monomers and demonstrated that electrostatic interactions with heparan sulfate and intermonomer hydrophobic interactions work in concert to stabilize the dimer. The importance of oligomerization was demonstrated by inhibition of signaling with a new epitope-defined monoclonal antibody that specifically targets oligomerization. These findings indicate that RAGE-heparan sulfate oligomeric complexes are essential for signaling and that interfering with RAGE oligomerization might be of therapeutic value.

PubMed: 23679870
DOI: 10.1021/cb4001553

実験手法

X-RAY DIFFRACTION (3.503 Å)