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

Liang, Wenguang G.; Wijaya, Juwina; Wei, Hui; Noble, Alex J.; Mancl, Jordan M.; Mo, Swansea; Lee, David; Lin King, John V.; Pan, Man; Liu, Chang; Koehler, Carla M.; Zhao, Minglei; Potter, Clinton S.; Carragher, Bridget; Li, Sheng; Tang, Wei-Jen

doi:10.1038/s41467-022-29322-4

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

Journal Article · Tue Apr 05 00:00:00 EDT 2022 · Nature Communications

DOI:https://doi.org/10.1038/s41467-022-29322-4· OSTI ID:1866449

Liang, Wenguang G. ^[1]; Wijaya, Juwina ^[2];

^[3];

^[3]; Mancl, Jordan M. ^[1]; Mo, Swansea ^[1];

^[4]; Lin King, John V. ^[5];

^[1]; Liu, Chang ^[1]; Koehler, Carla M. ^[2];

^[1]; Potter, Clinton S. ^[3];

^[3];

^[4];

^[1]

Univ. of Chicago, IL (United States)
Univ. of California, Los Angeles, CA (United States)
New York Structural Biology Center, New York, NY (United States). Simons Electron Microscopy Center
Univ. of California, San Diego, CA (United States)
Univ. of California, San Francisco, CA (United States)

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.

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Research Organization:: Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES); National Institutes of Health (NIH); Simons Foundation

Grant/Contract Number:: AC02-06CH11357; GM121964; GM103622; SF349247; GM103310; U24 GM129539

OSTI ID:: 1866449

Alternate ID(s):: OSTI ID: 1867483; OSTI ID: 1869887; OSTI ID: 1871739; OSTI ID: 1901328

Journal Information:: Nature Communications, Vol. 13, Issue 1; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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