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Ligand-specific conformational change drives interdomain allostery in Pin1

Author

Listed:
  • Alexandra Born

    (University of Colorado Anschutz Medical Campus, Department of Biochemistry and Molecular Genetics)

  • Janne Soetbeer

    (ETH Zürich, Vladimir-Prelog-Weg 2, ETH-Hönggerberg)

  • Morkos A. Henen

    (University of Colorado Anschutz Medical Campus, Department of Biochemistry and Molecular Genetics
    Mansoura University)

  • Frauke Breitgoff

    (ETH Zürich, Vladimir-Prelog-Weg 2, ETH-Hönggerberg)

  • Yevhen Polyhach

    (ETH Zürich, Vladimir-Prelog-Weg 2, ETH-Hönggerberg)

  • Gunnar Jeschke

    (ETH Zürich, Vladimir-Prelog-Weg 2, ETH-Hönggerberg)

  • Beat Vögeli

    (University of Colorado Anschutz Medical Campus, Department of Biochemistry and Molecular Genetics)

Abstract

Pin1 is a two-domain cell regulator that isomerizes peptidyl-prolines. The catalytic domain (PPIase) and the other ligand-binding domain (WW) sample extended and compact conformations. Ligand binding changes the equilibrium of the interdomain conformations, but the conformational changes that lead to the altered domain sampling were unknown. Prior evidence has supported an interdomain allosteric mechanism. We recently introduced a magnetic resonance-based protocol that allowed us to determine the coupling of intra- and interdomain structural sampling in apo Pin1. Here, we describe ligand-specific conformational changes that occur upon binding of pCDC25c and FFpSPR. pCDC25c binding doubles the population of the extended states compared to the virtually identical populations of the apo and FFpSPR-bound forms. pCDC25c binding to the WW domain triggers conformational changes to propagate via the interdomain interface to the catalytic site, while FFpSPR binding displaces a helix in the PPIase that leads to repositioning of the PPIase catalytic loop.

Suggested Citation

  • Alexandra Born & Janne Soetbeer & Morkos A. Henen & Frauke Breitgoff & Yevhen Polyhach & Gunnar Jeschke & Beat Vögeli, 2022. "Ligand-specific conformational change drives interdomain allostery in Pin1," Nature Communications, Nature, vol. 13(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32340-x
    DOI: 10.1038/s41467-022-32340-x
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    References listed on IDEAS

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    1. Hongwu Zheng & Han You & Xiao Zhen Zhou & Stephen A. Murray & Takafumi Uchida & Gerburg Wulf & Ling Gu & Xiaoren Tang & Kun Ping Lu & Zhi-Xiong Jim Xiao, 2002. "The prolyl isomerase Pin1 is a regulator of p53 in genotoxic response," Nature, Nature, vol. 419(6909), pages 849-853, October.
    2. Hongwu Zheng & Han You & Xiao Zhen Zhou & Stephen A. Murray & Takafumi Uchida & Gerburg Wult & Ling Gu & Xiaoren Tang & Kun Ping Lu & Zhi-Xiong Jim Xiao, 2002. "Erratum: The prolyl isomerase Pin1 is a regulator of p53 in genotoxic response," Nature, Nature, vol. 420(6914), pages 445-445, November.
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