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Structural basis for the mechanisms of human presequence protease conformational switch and substrate recognition

Author

Listed:
  • Wenguang G. Liang

    (Ben-May Department for Cancer Research, The University of Chicago)

  • Juwina Wijaya

    (University of California Los Angeles)

  • Hui Wei

    (National Resource for Automated Molecular Microscopy, Simons Electron Microscopy Center, New York Structural Biology Center)

  • Alex J. Noble

    (National Resource for Automated Molecular Microscopy, Simons Electron Microscopy Center, New York Structural Biology Center)

  • Jordan M. Mancl

    (Ben-May Department for Cancer Research, The University of Chicago)

  • Swansea Mo

    (Ben-May Department for Cancer Research, The University of Chicago)

  • David Lee

    (University of California San Diego)

  • John V. Lin King

    (University of California, San Francisco)

  • Man Pan

    (The University of Chicago)

  • Chang Liu

    (The University of Chicago)

  • Carla M. Koehler

    (University of California Los Angeles)

  • Minglei Zhao

    (The University of Chicago)

  • Clinton S. Potter

    (National Resource for Automated Molecular Microscopy, Simons Electron Microscopy Center, New York Structural Biology Center)

  • Bridget Carragher

    (National Resource for Automated Molecular Microscopy, Simons Electron Microscopy Center, New York Structural Biology Center)

  • Sheng Li

    (University of California San Diego)

  • Wei-Jen Tang

    (Ben-May Department for Cancer Research, The University of Chicago)

Abstract

Presequence protease (PreP), a 117 kDa mitochondrial M16C metalloprotease vital for mitochondrial proteostasis, degrades presequence peptides cleaved off from nuclear-encoded proteins and other aggregation-prone peptides, such as amyloid β (Aβ). PreP structures have only been determined in a closed conformation; thus, the mechanisms of substrate binding and selectivity remain elusive. Here, we leverage advanced vitrification techniques to overcome the preferential denaturation of one of two ~55 kDa homologous domains of PreP caused by air-water interface adsorption. Thereby, we elucidate cryoEM structures of three apo-PreP open states along with Aβ- and citrate synthase presequence-bound PreP at 3.3–4.6 Å resolution. Together with integrative biophysical and pharmacological approaches, these structures reveal the key stages of the PreP catalytic cycle and how the binding of substrates or PreP inhibitor drives a rigid body motion of the protein for substrate binding and catalysis. Together, our studies provide key mechanistic insights into M16C metalloproteases for future therapeutic innovations.

Suggested Citation

  • Wenguang G. Liang & Juwina Wijaya & Hui Wei & Alex J. Noble & Jordan M. Mancl & Swansea Mo & David Lee & John V. Lin King & Man Pan & Chang Liu & Carla M. Koehler & Minglei Zhao & Clinton S. Potter & , 2022. "Structural basis for the mechanisms of human presequence protease conformational switch and substrate recognition," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29322-4
    DOI: 10.1038/s41467-022-29322-4
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    References listed on IDEAS

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    1. Ka Young Chung & Søren G. F. Rasmussen & Tong Liu & Sheng Li & Brian T. DeVree & Pil Seok Chae & Diane Calinski & Brian K. Kobilka & Virgil L. Woods & Roger K. Sunahara, 2011. "Conformational changes in the G protein Gs induced by the β2 adrenergic receptor," Nature, Nature, vol. 477(7366), pages 611-615, September.
    2. Rebecca Deprez-Poulain & Nathalie Hennuyer & Damien Bosc & Wenguang G. Liang & Emmanuelle Enée & Xavier Marechal & Julie Charton & Jane Totobenazara & Gonzague Berte & Jouda Jahklal & Tristan Verdelet, 2015. "Catalytic site inhibition of insulin-degrading enzyme by a small molecule induces glucose intolerance in mice," Nature Communications, Nature, vol. 6(1), pages 1-13, November.
    3. Juan Pablo Maianti & Amanda McFedries & Zachariah H. Foda & Ralph E. Kleiner & Xiu Quan Du & Malcolm A. Leissring & Wei-Jen Tang & Maureen J. Charron & Markus A. Seeliger & Alan Saghatelian & David R., 2014. "Anti-diabetic activity of insulin-degrading enzyme inhibitors mediated by multiple hormones," Nature, Nature, vol. 511(7507), pages 94-98, July.
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