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

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, Bridget Carragher, Sheng Li and Wei-Jen Tang ()
Additional contact information
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

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-29322-4

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