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Cis-trans isomerization of peptoid residues in the collagen triple-helix

Author

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  • Rongmao Qiu

    (the Fifth Affiliated Hospital, Sun Yat-sen University
    the Fifth Affiliated Hospital, Sun Yat-sen University)

  • Xiaojing Li

    (the Fifth Affiliated Hospital, Sun Yat-sen University
    the Fifth Affiliated Hospital, Sun Yat-sen University)

  • Kui Huang

    (the Fifth Affiliated Hospital, Sun Yat-sen University
    the Fifth Affiliated Hospital, Sun Yat-sen University)

  • Weizhe Bai

    (the Fifth Affiliated Hospital, Sun Yat-sen University)

  • Daoning Zhou

    (the Fifth Affiliated Hospital, Sun Yat-sen University
    the Fifth Affiliated Hospital, Sun Yat-sen University)

  • Gang Li

    (the Fifth Affiliated Hospital, Sun Yat-sen University)

  • Zhao Qin

    (Syracuse University)

  • Yang Li

    (the Fifth Affiliated Hospital, Sun Yat-sen University
    the Fifth Affiliated Hospital, Sun Yat-sen University
    the Fifth Affiliated Hospital, Sun Yat-sen University)

Abstract

Cis-peptide bonds are rare in proteins, and building blocks less favorable to the trans-conformer have been considered destabilizing. Although proline tolerates the cis-conformer modestly among all amino acids, for collagen, the most prevalent proline-abundant protein, all peptide bonds must be trans to form its hallmark triple-helix structure. Here, using host-guest collagen mimetic peptides (CMPs), we discover that surprisingly, even the cis-enforcing peptoid residues (N-substituted glycines) form stable triple-helices. Our interrogations establish that these peptoid residues entropically stabilize the triple-helix by pre-organizing individual peptides into a polyproline-II helix. Moreover, noting that the cis-demanding peptoid residues drastically reduce the folding rate, we design a CMP whose triple-helix formation can be controlled by peptoid cis-trans isomerization, enabling direct targeting of fibrotic remodeling in myocardial infarction in vivo. These findings elucidate the principles of peptoid cis-trans isomerization in protein folding and showcase the exploitation of cis-amide-favoring residues in building programmable and functional peptidomimetics.

Suggested Citation

  • Rongmao Qiu & Xiaojing Li & Kui Huang & Weizhe Bai & Daoning Zhou & Gang Li & Zhao Qin & Yang Li, 2023. "Cis-trans isomerization of peptoid residues in the collagen triple-helix," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43469-8
    DOI: 10.1038/s41467-023-43469-8
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    References listed on IDEAS

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    1. Ronald J. Vagnozzi & Marjorie Maillet & Michelle A. Sargent & Hadi Khalil & Anne Katrine Z. Johansen & Jennifer A. Schwanekamp & Allen J. York & Vincent Huang & Matthias Nahrendorf & Sakthivel Sadayap, 2020. "An acute immune response underlies the benefit of cardiac stem cell therapy," Nature, Nature, vol. 577(7790), pages 405-409, January.
    2. Steven K. Holmgren & Kimberly M. Taylor & Lynn E. Bretscher & Ronald T. Raines, 1998. "Code for collagen's stability deciphered," Nature, Nature, vol. 392(6677), pages 666-667, April.
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