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Chemical synthesis and spontaneous folding of a multidomain protein: anticoagulant microprotein S

Academic Article
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Overview

authors

  • Hackeng, T. M.
  • Fernandez, J. A.
  • Dawson, Philip
  • Kent, S. B. H.
  • Griffin, John

publication date

  • 2000

journal

  • Proceedings of the National Academy of Sciences of the United States of America  Journal

abstract

  • Because of recent high-yield native ligation techniques, chemical synthesis of larger multidomain bioactive proteins is rapidly coming within reach. Here we describe the total chemical synthesis of a designed "microprotein S," comprising the gamma-carboxyglutamic acid-rich module, the thrombin-sensitive module, and the first epidermal growth factor-like module of human plasma protein S (residues 1-116). Synthetic microprotein S expressed anticoagulant cofactor activity for activated protein C in the down-regulation of blood coagulation, and the anticoagulant activity of microprotein S was not neutralized by C4b-binding protein, a natural inhibitor of native protein S in plasma. The correct folding of this complex multidomain protein was enhanced compared with individual modules because the gamma-carboxyglutamic acid-rich module and the thrombin-sensitive module markedly facilitated correct folding of the first epidermal growth factor-like module compared with folding of the first epidermal growth factor-like module alone. These results demonstrate that total chemical synthesis of proteins offers an effective way to generate multidomain biologically active proteins.

subject areas

  • 1-Carboxyglutamic Acid
  • Amino Acid Sequence
  • Anticoagulants
  • Epidermal Growth Factor
  • Humans
  • Molecular Sequence Data
  • Protein Folding
  • Protein S
  • Protein Structure, Tertiary
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Identity

PubMed Central ID

  • PMC18873

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.260239797

PubMed ID

  • 11106381
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Additional Document Info

start page

  • 14074

end page

  • 14078

volume

  • 97

issue

  • 26

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