Collagen is the most abundant protein in humans, comprising 1/3 of the total protein and 3/4 of the dry weight of skin. Collagen abnormalities are associated with many human diseases, including arthritis. The long-term objective of the proposed research is to reveal in atomic detail the chemical basis for the unique triple-helical structure of collagen, and to devise new therapies based on that knowledge.
Specific Aims. The five Specific Aims of this research proposal apply methods and ideas from physical organic chemistry, peptide chemistry, molecular self-assembly, chemical enzymology, and matrix biology.
Aim 1 is to assess the contribution of fundamental physicochemical forces to triple-helix stability.
Aim 2 is to test the hypothesis that a newly revealed force-the hyperconjugative n* interaction-links the backbone atoms in a polypeptide chain and thereby contributes to the conformational stability of collagen-related structures.
Aim 3 is to create collagen fragments and strands that self-assemble into human-scale triple helices.
Aim 4 is to gain insight into the mechanism of catalysis by human prolyl 4-hydroxylase, which is the enzyme that installs the prevalent and important 4-hydroxyproline residues in collagen strands. Finally, Aim 5 is to use extant knowledge of collagen to develop a new means to assess and heal pathologic wounds in an animal. Significance: The results of the research proposed herein will provide fundamental insights into the structure and conformational stability of the collagen triple helix, and will use those insights to create collagen mimics and collagen-based biomaterials with important therapeutic applications.

Public Health Relevance

This research project is focused on collagen, which is the most abundant protein in humans. Collagen abnormalities are associated with a variety of human diseases, including arthritis. The goal of the project is to obtain insights into the relationship between the amino acid sequence of collagen and its biological function (or dysfunction), as well as to create novel collagen-like proteins of potential therapeutic use.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-BCMB-A (02))
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Tseng, Hung H
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University of Wisconsin Madison
Schools of Earth Sciences/Natur
United States
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Tanrikulu, I Caglar; Forticaux, Audrey; Jin, Song et al. (2016) Peptide tessellation yields micrometre-scale collagen triple helices. Nat Chem 8:1008-1014
Vasta, James D; Andersen, Kristen A; Deck, Kathryn M et al. (2016) Selective Inhibition of Collagen Prolyl 4-Hydroxylase in Human Cells. ACS Chem Biol 11:193-9
Vasta, James D; Choudhary, Amit; Jensen, Katrina H et al. (2016) Prolyl 4-Hydroxylase: Substrate Isosteres in Which an (E)- or (Z)-Alkene Replaces the Prolyl Peptide Bond. Biochemistry :
Vasta, James D; Raines, Ronald T (2016) Human Collagen Prolyl 4-Hydroxylase Is Activated by Ligands for Its Iron Center. Biochemistry 55:3224-33
Newberry, Robert W; Raines, Ronald T (2016) A prevalent intraresidue hydrogen bond stabilizes proteins. Nat Chem Biol 12:1084-1088
Newberry, R W; Raines, R T (2016) Crystal structure of N-(3-oxo-butano-yl)-l-homoserine lactone. Acta Crystallogr E Crystallogr Commun 72:136-9
Newberry, Robert W; Orke, Samuel J; Raines, Ronald T (2016) n→π* Interactions Are Competitive with Hydrogen Bonds. Org Lett 18:3614-7
Chattopadhyay, Sayani; Guthrie, Kathleen M; Teixeira, Leandro et al. (2016) Anchoring a cytoactive factor in a wound bed promotes healing. J Tissue Eng Regen Med 10:1012-1020
Arnold, Ulrich; Raines, Ronald T (2016) Replacing a single atom accelerates the folding of a protein and increases its thermostability. Org Biomol Chem 14:6780-5
Vasta, James D; Raines, Ronald T (2015) Selective inhibition of prolyl 4-hydroxylases by bipyridinedicarboxylates. Bioorg Med Chem 23:3081-90

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