National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
GM121964
United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
GM103622
United States
Simons Foundation
SF349247
United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
GM103310
United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
U24GM129539
United States
Department of Energy (DOE, United States)
DE-AC02-06CH11357
United States
Citation
Journal: Nat Commun / Year: 2022 Title: Structural basis for the mechanisms of human presequence protease conformational switch and substrate recognition. Authors: 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 ...Authors: 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 / Wei-Jen Tang / 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 ...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.
EMPIAR-10929 (Title: CryoET of presequence protease single particle / Data size: 25.4 Data #1: Unaligned K2 tilt image frame stacks [micrographs - multiframe] Data #2: Binned by 4 tomograms from all 7 tilt-series [reconstructed volumes])
Film or detector model: GATAN K2 QUANTUM (4k x 4k) / Detector mode: COUNTING / Average electron dose: 4.0 e/Å2 / Details: See EMPIAR entry for details.
Electron beam
Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
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