- EMDB-32286: Structure of USP14-bound human 26S proteasome in state EA2.0_UBL ... -
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基本情報
登録情報
データベース: EMDB / ID: EMD-32286
タイトル
Structure of USP14-bound human 26S proteasome in state EA2.0_UBL with the local RPN1 density improved
マップデータ
Map of the human 26S proteasome in state EA2.0_UBL, with the RP/CP low-pass filtered to 3.8/2.8 angstrom and sharpened by a B-factor of -60/0, rescaled to the pixel size of 0.685 angstrom
National Natural Science Foundation of China (NSFC)
11774012
中国
引用
ジャーナル: Nature / 年: 2022 タイトル: USP14-regulated allostery of the human proteasome by time-resolved cryo-EM. 著者: Shuwen Zhang / Shitao Zou / Deyao Yin / Lihong Zhao / Daniel Finley / Zhaolong Wu / Youdong Mao / 要旨: Proteasomal degradation of ubiquitylated proteins is tightly regulated at multiple levels. A primary regulatory checkpoint is the removal of ubiquitin chains from substrates by the deubiquitylating ...Proteasomal degradation of ubiquitylated proteins is tightly regulated at multiple levels. A primary regulatory checkpoint is the removal of ubiquitin chains from substrates by the deubiquitylating enzyme ubiquitin-specific protease 14 (USP14), which reversibly binds the proteasome and confers the ability to edit and reject substrates. How USP14 is activated and regulates proteasome function remain unknown. Here we present high-resolution cryo-electron microscopy structures of human USP14 in complex with the 26S proteasome in 13 distinct conformational states captured during degradation of polyubiquitylated proteins. Time-resolved cryo-electron microscopy analysis of the conformational continuum revealed two parallel pathways of proteasome state transitions induced by USP14, and captured transient conversion of substrate-engaged intermediates into substrate-inhibited intermediates. On the substrate-engaged pathway, ubiquitin-dependent activation of USP14 allosterically reprograms the conformational landscape of the AAA-ATPase motor and stimulates opening of the core particle gate, enabling observation of a near-complete cycle of asymmetric ATP hydrolysis around the ATPase ring during processive substrate unfolding. Dynamic USP14-ATPase interactions decouple the ATPase activity from RPN11-catalysed deubiquitylation and kinetically introduce three regulatory checkpoints on the proteasome, at the steps of ubiquitin recognition, substrate translocation initiation and ubiquitin chain recycling. These findings provide insights into the complete functional cycle of the USP14-regulated proteasome and establish mechanistic foundations for the discovery of USP14-targeted therapies.
ダウンロード / ファイル: emd_32286.map.gz / 形式: CCP4 / 大きさ: 1000 MB / タイプ: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
注釈
Map of the human 26S proteasome in state EA2.0_UBL, with the RP/CP low-pass filtered to 3.8/2.8 angstrom and sharpened by a B-factor of -60/0, rescaled to the pixel size of 0.685 angstrom
ボクセルのサイズ
X=Y=Z: 0.685 Å
密度
表面レベル
登録者による: 0.028
最小 - 最大
-0.010300144 - 0.10411645
平均 (標準偏差)
0.0016216476 (±0.005108043)
対称性
空間群: 1
詳細
EMDB XML:
マップ形状
Axis order
X
Y
Z
Origin
0
0
0
サイズ
640
640
640
Spacing
640
640
640
セル
A=B=C: 438.4 Å α=β=γ: 90.0 °
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添付データ
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追加マップ: Unfiltered, unsharpened map of the human 26S proteasome...