C-terminal glutamine acts as a C-degron targeted by E3 ubiquitin ligase TRIM7.
C-terminal glutamine acts as a C-degron targeted by E3 ubiquitin ligase TRIM7.
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C 末端谷氨酰胺充当 E3 泛素连接酶 TRIM7 靶向的 C 降解决定子
DOI：
10.1073/pnas.2203218119
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发表时间：
2022-07-26
影响因子：
11.1
通讯作者：
Dong, Cheng
中科院分区：
文献类型：
--
作者：
Ru, Yawei;Yan, Xiaojie;Zhang, Bing;Song, Lili;Feng, Qiqi;Ye, Chen;Zhou, Zhili;Yang, Zhenzhen;Li, Yao;Zhang, Zhenjian;Li, Qianqian;Mi, Wenyi;Dong, Cheng
靶向蛋白质降解保护细胞免受异常或异源蛋白质的干扰。E3泛素连接酶TRIM 7被鉴定为通过靶向病毒2BC蛋白进行蛋白酶体依赖性降解来限制肠道病毒复制的抗病毒效应物。在这里，我们发现TRIM 7通过其B30.2结构域特异性识别一般的C-末端谷氨酰胺残基，并靶向具有Gln/C-degron的2BC蛋白，以通过Gln/C-degron途径降解。我们目前的晶体结构的TRIM7B30.2绑定到各种肽结束的C-末端谷氨酰胺。通过突变和生化分析相结合的方法，我们初步阐明了TRIM 7 B30. 2对Gln/C-degron的识别机制。蛋白质的暴露的N-末端或C-末端残基可以在同源序列背景下充当降解信号（降解决定子），其被特异性E3泛素连接酶靶向，用于通过N-降解决定子或C-降解决定子途径的蛋白酶体依赖性降解。在这里，我们发现了一个独特的C-降解决定子途径，称为谷氨酰胺/C-降解决定子途径，其中E3泛素连接酶TRIM 7（TRIM7B30.2）的B30.2结构域介导的识别蛋白携带的C-末端谷氨酰胺。通过确定TRIM7B30.2与各种肽的复合物的晶体结构，我们表明TRIM7B30.2形成带正电荷的结合口袋以接合“U”形Gln/C-degron。底物的四个C-末端残基在C-降解决定子识别中起重要作用，其中C-末端谷氨酰胺是主要决定子。体外生化和细胞实验用于进一步分析底物特异性和TRIM 7对Gln/C-degron的选择性降解。
Targeted protein degradation protects cells from disturbance of abnormal or heterologous proteins. E3 ubiquitin ligase TRIM7 is identified as an antiviral effector that restricts enterovirus replication through targeting of the viral 2BC protein for proteasome-dependent degradation. Here, we found that TRIM7 specifically recognizes a general C-terminal glutamine residue by its B30.2 domain and targets 2BC protein bearing a Gln/C-degron for degradation through the Gln/C–degron pathway. We present crystal structures of TRIM7B30.2 bound to various peptides ending with C-terminal glutamine. By combining mutagenesis and biochemical analyses, we delineated the recognition mechanism of Gln/C-degron by TRIM7B30.2. The exposed N-terminal or C-terminal residues of proteins can act, in cognate sequence contexts, as degradation signals (degrons) that are targeted by specific E3 ubiquitin ligases for proteasome-dependent degradation by N-degron or C-degron pathways. Here, we discovered a distinct C-degron pathway, termed the Gln/C-degron pathway, in which the B30.2 domain of E3 ubiquitin ligase TRIM7 (TRIM7B30.2) mediates the recognition of proteins bearing a C-terminal glutamine. By determining crystal structures of TRIM7B30.2 in complexes with various peptides, we show that TRIM7B30.2 forms a positively charged binding pocket to engage the “U”-shaped Gln/C-degron. The four C-terminal residues of a substrate play an important role in C-degron recognition, with C-terminal glutamine as the principal determinant. In vitro biochemical and cellular experiments were used to further analyze the substrate specificity and selective degradation of the Gln/C-degron by TRIM7.
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影响因子：
16
作者：
Lin HC;Yeh CW;Chen YF;Lee TT;Hsieh PY;Rusnac DV;Lin SY;Elledge SJ;Zheng N;Yen HS
通讯作者：
Yen HS
影响因子：
44.1
作者：
Hu H;Sun SC
通讯作者：
Sun SC
影响因子：
64.5
作者：
Koren I;Timms RT;Kula T;Xu Q;Li MZ;Elledge SJ
通讯作者：
Elledge SJ
影响因子：
21.3
作者：
Davies, Clare C.;Chakraborty, Atanu;Behrens, Axel
通讯作者：
Behrens, Axel
影响因子：
21.3
作者：
Hwang, Cheol-Sang;Shemorry, Anna;Auerbach, Daniel;Varshavsky, Alexander
通讯作者：
Varshavsky, Alexander