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Title page for ETD etd-03242013-212240


Type of Document Dissertation
Author Cummings, Christopher Franklin
URN etd-03242013-212240
Title Formation and Function of Collagen IV Sulfilimine Bonds
Degree PhD
Department Biochemistry
Advisory Committee
Advisor Name Title
Dr. Billy Hudson Committee Chair
Dr. Charles R. Sanders Committee Member
Dr. Fred Guengerich Committee Member
Dr. Kevin Strange Committee Member
Keywords
  • Collagen IV
  • Peroxidasin
  • Bromide
  • Chloride
  • Hypohalous Acid
  • Basement Membrane
  • Sulfilimine Bond
Date of Defense 2012-12-19
Availability unrestricted
Abstract
Collagen IV networks are essential for animal viability, providing a stable extracellular foundation for tissue functioning. These networks contain sulfilimine bonds that covalently crosslink the C-terminal NC1 interfaces of adjoining collagen IV protomers. Bond formation occurs within basement membranes as the enzymatic product of peroxidasin through a mechanism that utilizes hypohalous acids as chemical intermediates. Within this context, the halide ions bromide and chloride have distinct roles in the formation of collagen IV networks. Mechanistic studies in matrix demonstrated that peroxidasin forms sulflimine bonds via its halogenation cycle, oxidizing bromide ions into hypobromous acid which then catalyze bond formation. In contrast to the role of bromide during bond formation, chloride has emerged as a critical element during the process of assembling NC1 domains into a suitable substrate for peroxidasin. Altogether, the reaction hinges on the sequential action of both halides. Empirical data presented herein demonstrates that sulfilimine bonds functionally reinforce the NC1 hexamer substrate. Thus, sulfilimine bonds are key structural elements of collagen IV networks, forming through the extracellular catalytic activity of peroxidasin and the coordinated functioning of bromide and chloride ions. These advancements delineate an orchestrated pathway of enzymology and chemistry that assembles the extracellular bedrock of tissue physiology.
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