6XOS
CryoEM structure of human presequence protease in partial open state 1
Summary for 6XOS
Entry DOI | 10.2210/pdb6xos/pdb |
EMDB information | 22278 22279 22280 22281 22282 |
Descriptor | Presequence protease, mitochondrial (1 entity in total) |
Functional Keywords | partial open state, hydrolase |
Biological source | Homo sapiens (Human) |
Total number of polymer chains | 1 |
Total formula weight | 114901.46 |
Authors | Liang, W.G.,Zhao, M.,Tang, W. (deposition date: 2020-07-07, release date: 2021-07-07, Last modification date: 2024-05-15) |
Primary citation | Liang, W.G.,Wijaya, J.,Wei, H.,Noble, A.J.,Mancl, J.M.,Mo, S.,Lee, D.,Lin King, J.V.,Pan, M.,Liu, C.,Koehler, C.M.,Zhao, M.,Potter, C.S.,Carragher, B.,Li, S.,Tang, W.J. Structural basis for the mechanisms of human presequence protease conformational switch and substrate recognition. Nat Commun, 13:1833-1833, 2022 Cited by PubMed 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. PubMed: 35383169DOI: 10.1038/s41467-022-29322-4 PDB entries with the same primary citation |
Experimental method | ELECTRON MICROSCOPY (3.7 Å) |
Structure validation
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