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Title page for ETD etd-05302007-114804


Type of Document Dissertation
Author Dattilo, Brian Matthew
URN etd-05302007-114804
Title Structural characterization of the receptor for advanced glycation end products reveals a two domain modular architecture
Degree PhD
Department Biochemistry
Advisory Committee
Advisor Name Title
Walter J. Chazin Committee Chair
Billy G. Hudson Committee Member
Charles R. Sanders, II Committee Member
Martin Egli Committee Member
Keywords
  • Structural Biology
  • RAGE
  • Receptor for Advanced Glycation End Products
  • Soluble RAGE
  • Receptor Signaling
  • S100 Proteins
  • Ligands (Biochemistry)
Date of Defense 2007-05-14
Availability unrestricted
Abstract
The Receptor for Advanced Glycation End Products (RAGE) contains a single transmembrane helix, a small cytosolic domain, and an extracellular region (sRAGE) composed of three Ig-like domains (V, C1, C2). RAGE has been implicated in complications arising from diabetes and chronic inflammation and is widely thought to be a therapeutic target. In this dissertation, production of purified sRAGE and the five single and tandem domain constructs enabled biophysical and structural characterization. The results, including an x-ray crystal structure of VC1, show that the V and C1 domains form an integrated structural unit. In contrast, C2 is attached to VC1 by a flexible linker and is fully independent. Studies of the interaction with a known RAGE ligand, Ca2+-S100B, revealed a major contribution from the V domain but clearly defined contributions to binding from the C1 domain. The implications of these results are discussed with respect to models for sRAGE quaternary structure and RAGE signaling.
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