6XOU

CryoEM structure of human presequence protease in open state

6XOU の概要

• エントリーDOI: 10.2210/pdb6xou/pdb
• EMDBエントリー: 22278 22279 22280 22281 22282
• 分子名称: Presequence protease, mitochondrial (1 entity in total)
• 機能のキーワード: partial open state, hydrolase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 114901.46

構造登録者

Liang, W.G.,Zhao, M.,Tang, W. (登録日: 2020-07-07, 公開日: 2021-07-07, 最終更新日: 2025-05-14)

主引用文献

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

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: 35383169
DOI: 10.1038/s41467-022-29322-4

実験手法

ELECTRON MICROSCOPY (4 Å)