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-Structure paper
タイトル | Structural basis for the mechanisms of human presequence protease conformational switch and substrate recognition. |
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ジャーナル・号・ページ | Nat Commun, Vol. 13, Issue 1, Page 1833, Year 2022 |
掲載日 | 2022年4月5日 |
著者 | 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 / |
PubMed 要旨 | 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. |
リンク | Nat Commun / PubMed:35383169 / PubMed Central |
手法 | EM (単粒子) / EM (トモグラフィー) |
解像度 | 3.3 - 4.0 Å |
構造データ | EMDB-22278, PDB-6xos: EMDB-22279, PDB-6xot: EMDB-22280, PDB-6xou: EMDB-22281, PDB-6xov: EMDB-25921: |
由来 |
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キーワード | HYDROLASE / Partial open state |