title: Solution structure of the soluble receptor for advanced glycation end products (sRAGE).
abstract: The receptor for advanced glycation end products (RAGE) is a multiligand cell surface receptor involved in various human diseases, as it binds to numerous molecules and proteins that modulate the activity of other proteins. Elucidating the three-dimensional structure of this receptor is therefore most important for understanding its function during activation and cellular signaling. The major alternative splice product of RAGE comprises its extracellular region that occurs as a soluble protein (sRAGE). Although the structures of sRAGE domains were available, their assembly into the functional full-length protein remained unknown. We observed that the protein has concentration-dependent oligomerization behavior, and this is also mediated by the presence of Ca(2+) ions. Moreover, using synchrotron small angle x-ray scattering, the solution structure of human sRAGE was determined in the monomeric and dimeric forms. The model for the monomer displays a J-like shape, whereas the dimer is formed through the association of the two N-terminal domains and has an elongated structure. These results provide insights into the assembly of the RAGE homodimer, which is essential for signal transduction, and the sRAGE:RAGE heterodimer that leads to blockage of the receptor signaling, paving the way for the design of therapeutic strategies for a large number of different pathologies.
authors.affiliation: Institute for Molecular and Cell Biology, University of Porto, 4150-180 Porto, Portugal.
authors.forename: Zsuzsa
authors.initials: Z
authors.lastname: Sárkány
authors.forename: Teemu P
authors.initials: TP
authors.lastname: Ikonen
authors.forename: Frederico
authors.initials: F
authors.lastname: Ferreira-da-Silva
authors.forename: Maria João
authors.initials: MJ
authors.lastname: Saraiva
authors.forename: Dmitri
authors.initials: D
authors.lastname: Svergun
authors.forename: Ana Margarida
authors.initials: AM
authors.lastname: Damas
mesh_terms: D002118:Calcium / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D019906:Nuclear Magnetic Resonance, Biomolecular; D055503:Protein Multimerization / Q000502:physiology*; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D002118:Calcium