Date of Award

1-1-2017

Language

English

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

College/School/Department

Department of Chemistry

Content Description

1 online resource (ii, xiv, 161 pages) : illustrations (some color)

Dissertation/Thesis Chair

Alexander Shekhtman

Committee Members

Li Niu, Jayanti Pande, Jia Sheng

Keywords

protein NMR, RAGE-DIAPH1 interaction, SAR, signal transduction, small molecule inhibitor, the receptor of advanced glycation end products, Glycosylation, Glycoproteins, Ligand binding (Biochemistry), Fluorescence spectroscopy, Transduction

Subject Categories

Biochemistry | Organic Chemistry | Pharmacy and Pharmaceutical Sciences

Abstract

The receptor of advanced glycation end product (RAGE) is a multiligand receptor of the immunoglobulin superfamily of cell surface molecules, which plays an important role in immune responses. Full-length RAGE includes three extracellular immunoglobulin domains, a transmembrane domain and an intracellular domain. It is a pattern recognition receptor that can bind diverse ligands. NMR spectroscopy and x-ray crystallization studies of the extracellular domains of RAGE indicate that RAGE ligands bind by distinct charge- and hydrophobicity-dependent mechanisms. It is found that calgranulin binding to the C1C2 domain or AGEs binding to the V domain activates extracellular signaling, which triggers interactions of the RAGE cytoplasmic tail (ctRAGE) with intracellular effector, such as diaphanous 1 (DIAPH1), to initiate signal transduction cascades. ctRAGE is essential for RAGE-ligand-mediated signal transduction and consequent modulation of gene expression and cellular properties. RAGE is over-expressed in diseased tissues of most RAGE-associated pathogenic conditions, such as complications of Alzheimer’s diseases, diabetes, vascular diseases, inflammation, cancers and neurodegeneration. They are the major diseases affecting a large population worldwide. RAGE can function as a biomarker or drug target for these diseases.

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