The Receptor for Advanced Glycation End-products (RAGE) is an immunoglobulin-type multiligand transmembrane protein expressed in numerous cell types. For instance, RAGE interaction with S100B leads to RAGE upregulation and initialization of a spiral proinflammatory associated with different neural disorders. The main goal of the presented project was to provide a comprehensive understanding of the structure of RAGE-ligand complexes and to explain the molecular mechanism of signal transduction by this receptor. By combining mass spectrometry-based methods, namely hydrogen-deuterium exchange, cross-linking analysis and native MS, available X-ray structural data, molecular dynamics and integrative molecular modelling we present a structural characterization of the hetero-oligomeric complex of the full-length RAGE with S100B. Our results show that RAGE functions as a tetramer exposing an extensive surface formed by V domains with shape and electrostatics charge suited for efficient S100B binding. Furthermore, HDX results 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.
This research was funded by EU CEPT (POIG.02.02.00-14-024/08-00), Foundation of Polish Science TEAM TECH CORE FACILITY/2016- 2/2, National Multidisciplinary Laboratory of Functional Nanomaterials (POIGT.02.02.00-00-025/09-00), National Science Centre, Poland MAESTRO (2014/14/A/NZ1/00306) and OPUS (2018/31/B/ST4/03809), POL-OPENSCREEN (DIR/WK/2018/06) from Ministry of Science and Higher Education, Antwerp University Research Fund for the Concerted Research Actions grant (BOF-GOA 4D protein structure) and Wellcome Trust multi-user equipment grant 208385/Z/17/Z. This research was supported by PLGrid Infrastructure.