{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Liang WG"],"funding":["Simons Foundation","NIGMS NIH HHS","U.S. Department of Health & Human Services | National Institutes of Health"],"pagination":["1833"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC8983764"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["13(1)"],"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, the"],"journal":["Nature communications"],"pubmed_title":["Structural basis for the mechanisms of human presequence protease conformational switch and substrate recognition."],"pmcid":["PMC8983764"],"funding_grant_id":["GM 121964","R35 GM143052","SF349247","SF 349547","P41 GM103310","R01 GM121964","U24 GM129539","P41 GM103622","GM 103310"],"pubmed_authors":["Tang WJ","Noble AJ","Carragher B","Koehler CM","Lin King JV","Potter CS","Lee D","Mancl JM","Mo S","Zhao M","Li S","Liang WG","Wei H","Liu C","Wijaya J","Pan M"],"additional_accession":[]},"is_claimable":false,"name":"Structural basis for the mechanisms of human presequence protease conformational switch and substrate recognition.","description":"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, the","dates":{"release":"2022-01-01T00:00:00Z","publication":"2022 Apr","modification":"2026-05-31T01:09:43.332Z","creation":"2025-04-03T22:51:37.724Z"},"accession":"S-EPMC8983764","cross_references":{"pubmed":["35383169"],"doi":["10.1038/s41467-022-29322-4"]}}