title: Change in the Molecular Dimension of a RAGE-Ligand Complex Triggers RAGE Signaling.
abstract: The weak oligomerization exhibited by many transmembrane receptors has a profound effect on signal transduction. The phenomenon is difficult to characterize structurally due to the large sizes of and transient interactions between monomers. The receptor for advanced glycation end products (RAGE), a signaling molecule central to the induction and perpetuation of inflammatory responses, is a weak constitutive oligomer. The RAGE domain interaction surfaces that mediate homo-dimerization were identified by combining segmental isotopic labeling of extracellular soluble RAGE (sRAGE) and nuclear magnetic resonance spectroscopy with chemical cross-linking and mass spectrometry. Molecular modeling suggests that two sRAGE monomers orient head to head forming an asymmetric dimer with the C termini directed toward the cell membrane. Ligand-induced association of RAGE homo-dimers on the cell surface increases the molecular dimension of the receptor, recruiting Diaphanous 1 (DIAPH1) and activating signaling pathways.
authors.affiliation: Department of Chemistry, State University of New York at Albany, Albany, NY 12222, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Xue
authors.affiliation: New York University, Langone Medical Center, New York, NY 10016, USA.
authors.forename: Michaele
authors.initials: M
authors.lastname: Manigrasso
authors.affiliation: Department of Chemistry, State University of New York at Albany, Albany, NY 12222, USA.
authors.forename: Matteo
authors.initials: M
authors.lastname: Scalabrin
authors.affiliation: Institute of Life Sciences, Bhubaneswar, Odisha 751023, India.
authors.forename: Vivek
authors.initials: V
authors.lastname: Rai
authors.affiliation: Department of Chemistry, State University of New York at Albany, Albany, NY 12222, USA.
authors.forename: Sergey
authors.initials: S
authors.lastname: Reverdatto
authors.affiliation: Department of Chemistry, State University of New York at Albany, Albany, NY 12222, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Burz
authors.affiliation: Department of Chemistry, State University of New York at Albany, Albany, NY 12222, USA.
authors.forename: Daniele
authors.initials: D
authors.lastname: Fabris
authors.affiliation: New York University, Langone Medical Center, New York, NY 10016, USA.
authors.forename: Ann Marie
authors.initials: AM
authors.lastname: Schmidt
authors.affiliation: Department of Chemistry, State University of New York at Albany, Albany, NY 12222, USA. Electronic address: ashekhtman@albany.edu.
authors.forename: Alexander
authors.initials: A
authors.lastname: Shekhtman
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D000951:Antigens, Neoplasm / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D003432:Cross-Linking Reagents / Q000737:chemistry; D000080865:Formins; D015870:Gene Expression; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008301:Maleimides / Q000737:chemistry; D020928:Mitogen-Activated Protein Kinases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D062105:Molecular Docking Simulation; D019906:Nuclear Magnetic Resonance, Biomolecular; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D013816:Thermodynamics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000951:Antigens, Neoplasm; D001426:Bacterial Proteins; D003432:Cross-Linking Reagents; C485182:Cyan Fluorescent Protein; C108962:DIAPH1 protein, human; D000080865:Formins; D008024:Ligands; D008164:Luminescent Proteins; D008301:Maleimides; D011994:Recombinant Proteins; C071675:sulfosuccinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate; C054562:yellow fluorescent protein, Bacteria; D049452:Green Fluorescent Proteins; C498978:MOK protein, human; D020928:Mitogen-Activated Protein Kinases
keywords: NMR spectroscopy; RAGE; cancer; diabetes; diaphanous 1; hybrid method of structure determination; inflammation; mass spectrometry; pattern recognition; receptor for advanced glycation end products; segmental labeling; signal transduction