Cryo-EM of mammalian PA28αβ-iCP immunoproteasome reveals a distinct mechanism of proteasome activation by PA28αβ.
Cryo-EM of mammalian PA28αβ-iCP immunoproteasome reveals a distinct mechanism of proteasome activation by PA28αβ.
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哺乳动物 PA28αβ-iCP 免疫蛋白酶体的冷冻电镜揭示了 PA28αβ 蛋白酶体激活的独特机制
DOI：
10.1038/s41467-021-21028-3
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发表时间：
2021-02-02
影响因子：
16.6
通讯作者：
Cong Y
中科院分区：
文献类型：
--
作者：
Chen J;Wang Y;Xu C;Chen K;Zhao Q;Wang S;Yin Y;Peng C;Ding Z;Cong Y
蛋白酶体激活剂PA 28 αβ通过与免疫蛋白酶体核心颗粒（iCP）结合影响MHC I类抗原呈递。然而，由于缺乏哺乳动物PA 28 αβ-iCP结构，PA 28 αβ如何调节蛋白酶体仍然是难以捉摸的。本文通过冷冻电镜（cryo-EM）以近原子分辨率展示了哺乳动物PA 28 αβ-iCP免疫蛋白酶体和游离iCP的完整结构，并通过XL-MS确定了PA 28 αβ和iCP之间的空间排列。我们的结构显示，PA 28 αβ略微向iCP的α3-α4侧倾斜，干扰了看门α2/3/4亚基的变构网络，导致部分开放的iCP门。我们发现PA 28 αβ与iCP的结合和激活机制与同七聚体TbPA 26或PfPA 28与组成型CP的结合和激活机制不同。我们的研究揭示了免疫蛋白酶体的酶活性刺激机制，并表明PA 28 αβ-iCP在进化过程中经历了深刻的重塑，以达到其目前的免疫应答功能水平。蛋白酶体激活剂PA 28 αβ通过与免疫蛋白酶体核心颗粒（iCP）结合影响MHC I类抗原呈递。哺乳动物PA 28 αβ -iCP免疫蛋白酶体和游离iCP的Cryo-EM结构与交联数据相结合，揭示了复杂的结构，并提示了独特的免疫蛋白酶体活化机制。
The proteasome activator PA28αβ affects MHC class I antigen presentation by associating with immunoproteasome core particles (iCPs). However, due to the lack of a mammalian PA28αβ-iCP structure, how PA28αβ regulates proteasome remains elusive. Here we present the complete architectures of the mammalian PA28αβ-iCP immunoproteasome and free iCP at near atomic-resolution by cryo-EM, and determine the spatial arrangement between PA28αβ and iCP through XL-MS. Our structures reveal a slight leaning of PA28αβ towards the α3-α4 side of iCP, disturbing the allosteric network of the gatekeeper α2/3/4 subunits, resulting in a partial open iCP gate. We find that the binding and activation mechanism of iCP by PA28αβ is distinct from those of constitutive CP by the homoheptameric TbPA26 or PfPA28. Our study sheds lights on the mechanism of enzymatic activity stimulation of immunoproteasome and suggests that PA28αβ-iCP has experienced profound remodeling during evolution to achieve its current level of function in immune response. The proteasome activator PA28αβ affects MHC class I antigen presentation by associating with immunoproteasome core particles (iCPs). Cryo-EM structures of the mammalian PA28αβ -iCP immunoproteasome and free iCP, combined with cross-linking data, reveal the complex architecture and suggest a distinct immunoproteasome activation mechanism.
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DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
64.8
作者：
DRISCOLL, J;BROWN, MG;MONACO, JJ
通讯作者：
MONACO, JJ
人类26S蛋白酶体动态调控的结构基础
DOI：
10.1073/pnas.1614614113
发表时间：
2016-11-15
影响因子：
11.1
作者：
Chen, Shuobing;Wu, Jiayi;Mao, Youdong
通讯作者：
Mao, Youdong
影响因子：
16.6
作者：
Bard JAM;Goodall EA;Greene ER;Jonsson E;Dong KC;Martin A
通讯作者：
Martin A
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH