A model of full-length RAGE in complex with S100B

Alexander Moysa*, Kamil Steczkiewicz, Dorota Niedzialek, Dietmar Hammerschmid, Lilia Zhukova, Frank Sobott, Michal Dadlez

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)989-1002.e6
JournalStructure
Volume29
Issue number9
DOIs
Publication statusPublished - 2 Sept 2021

Keywords

  • HDX-MS
  • membrane proteins
  • molecular modeling
  • native MS
  • RAGE
  • receptor for advanced glycation end products
  • structural proteomics
  • XL-MS

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