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Chemical synthesis and biotinylation of the thrombospondin domain TSR2

Academic Article
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Overview

related to degree

  • Tiefenbrunn Sample, Theresa, Ph.D. in Chemical Biology, Scripps Research 2004 - 2009

authors

  • Tiefenbrunn Sample, Theresa
  • Dawson, Philip

publication date

  • May 2009

journal

  • Protein Science  Journal

abstract

  • The type 1 repeat domain from thrombospondin has potent antiangiogenic activity and a structurally interesting fold, making it an attractive target for protein engineering. Chemical synthesis is an attractive approach for studying protein domains because it enables the use of unnatural amino acids for site-specific labeling and detailed structure-function analysis. Here, we demonstrate the first total chemical synthesis of the thrombospondin type 1 repeat domain by native chemical ligation. In addition to the natural domain, five sites for side chain modification were evaluated and two were found to be compatible with oxidative folding. Several challenges were encountered during peptide synthesis due to the functional complexity of the domain. These challenges were overcome by the use of new solid supports, scavengers, and the testing of multiple ligation sites. We also describe an unusual sequence-specific protecting group migration observed during cleavage resulting in +90 Da and +194 Da adducts. Synthetic access to this domain enables the synthesis of a number of variants that can be used to further our understanding of the biochemical interaction network of thrombospondin and provide insight into the structure and function of this important antitumorogenic protein domain.

subject areas

  • Amino Acid Sequence
  • Biotinylation
  • Chromatography, High Pressure Liquid
  • Humans
  • Models, Molecular
  • Molecular Sequence Data
  • Peptides
  • Protein Engineering
  • Protein Folding
  • Protein Interaction Domains and Motifs
  • Thrombospondin 1
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Research

keywords

  • angiogenesis
  • ligation
  • protein synthesis
  • thrombospondin
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Identity

PubMed Central ID

  • PMC2771299

International Standard Serial Number (ISSN)

  • 0961-8368

Digital Object Identifier (DOI)

  • 10.1002/pro.107

PubMed ID

  • 19384999
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Additional Document Info

start page

  • 970

end page

  • 979

volume

  • 18

issue

  • 5

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