A model of full-length RAGE in complex with S100B

• Published in: Structure (London) 2021-09, Vol.29 (9), p.989-1002.e6
• Main Authors: Moysa, Alexander, Steczkiewicz, Kamil, Niedzialek, Dorota, Hammerschmid, Dietmar, Zhukova, Lilia, Sobott, Frank, Dadlez, Michal
• Format: Article
• Language: English
• Subjects: Animals; Binding Sites; HDX-MS; Humans; membrane proteins; Molecular Docking Simulation; molecular modeling; native MS; Protein Binding; RAGE; receptor for advanced glycation end products; Receptor for Advanced Glycation End Products - chemistry; Receptor for Advanced Glycation End Products - metabolism; S100 Calcium Binding Protein beta Subunit - chemistry; S100 Calcium Binding Protein beta Subunit - metabolism; Signal Transduction; structural proteomics; XL-MS
• ISSN: 0969-2126; 1878-4186
• DOI: 10.1016/j.str.2021.04.002

The receptor for advanced glycation end products (RAGE) is an immunoglobulin-type multiligand transmembrane protein expressed in numerous cell types, including the central nervous system cells. RAGE interaction with S100B, released during brain tissue damage, leads to RAGE upregulation and initialization of a spiral proinflammatory associated with different neural disorders. Here, we present the structural characterization of the hetero-oligomeric complex of the full-length RAGE with S100B, obtained by a combination of mass spectrometry-based methods and molecular modeling. We predict that RAGE functions as a tightly packed tetramer exposing a positively charged surface formed by V domains for S100B binding. Based on HDX results we demonstrate an allosteric coupling of the distal extracellular V domains and the transmembrane region, indicating a possible mechanism of signal transmission by RAGE across the membrane. Our model provides an insight into RAGE-ligand interactions, providing a basis for the rational design of the therapeutic modifiers of its activity. [Display omitted] •A model of fl_RAGE-S100B complex was developed based on MS and molecular modeling•HDX shows coupling between RAGE extracellular V domain and intracellular CT domain•Oligomerization may affect RAGE CT for its interaction with downward signaling factors S100B is released during brain tissue damage. RAGE and S100B interact as oligomers and initialize an inflammatory response associated with different neural disorders. Moysa et al. structurally characterized the hetero-oligomeric complex of the full-length RAGE with S100B by a combination of mass spectrometry-based methods and molecular modeling.