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CRL4 识别 CCT5 双 Glu 降解基序依赖于 TRiC 组装。

Recognition of the CCT5 di-Glu degron by CRL4 is dependent on TRiC assembly.

机构信息

Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.

University of Basel, Basel, Switzerland.

出版信息

EMBO J. 2023 Feb 15;42(4):e112253. doi: 10.15252/embj.2022112253. Epub 2023 Jan 30.

DOI:10.15252/embj.2022112253
PMID:36715408
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9929631/
Abstract

Assembly Quality Control (AQC) E3 ubiquitin ligases target incomplete or incorrectly assembled protein complexes for degradation. The CUL4-RBX1-DDB1-DCAF12 (CRL4 ) E3 ligase preferentially ubiquitinates proteins that carry a C-terminal double glutamate (di-Glu) motif. Reported CRL4 di-Glu-containing substrates include CCT5, a subunit of the TRiC chaperonin. How DCAF12 engages its substrates and the functional relationship between CRL4 and CCT5/TRiC is currently unknown. Here, we present the cryo-EM structure of the DDB1-DCAF12-CCT5 complex at 2.8 Å resolution. DCAF12 serves as a canonical WD40 DCAF substrate receptor and uses a positively charged pocket at the center of the β-propeller to bind the C-terminus of CCT5. DCAF12 specifically reads out the CCT5 di-Glu side chains, and contacts other visible degron amino acids through Van der Waals interactions. The CCT5 C-terminus is inaccessible in an assembled TRiC complex, and functional assays demonstrate that DCAF12 binds and ubiquitinates monomeric CCT5, but not CCT5 assembled into TRiC. Our biochemical and structural results suggest a previously unknown role for the CRL4 E3 ligase in overseeing the assembly of a key cellular complex.

摘要

组装质量控制 (AQC) E3 泛素连接酶将未完成或组装不正确的蛋白质复合物作为靶标进行降解。CUL4-RBX1-DDB1-DCAF12 (CRL4) E3 连接酶优先泛素化带有 C 末端双谷氨酸 (di-Glu) 基序的蛋白质。已报道的 CRL4 含有 di-Glu 的底物包括 CCT5，一种 TRiC 伴侣蛋白的亚基。DCAF12 如何与它的底物结合以及 CRL4 和 CCT5/TRiC 之间的功能关系目前尚不清楚。在这里，我们展示了 DDB1-DCAF12-CCT5 复合物的冷冻电镜结构，分辨率为 2.8 Å。DCAF12 作为一种典型的 WD40 DCAF 底物受体，利用 β- 桨叶中心的正电荷口袋结合 CCT5 的 C 末端。DCAF12 特异性读取 CCT5 的 di-Glu 侧链，并通过范德华相互作用与其他可见的降解基序氨基酸接触。在组装的 TRiC 复合物中，CCT5 的 C 末端无法接近，功能测定表明 DCAF12 结合并泛素化单体 CCT5，但不结合组装成 TRiC 的 CCT5。我们的生化和结构结果表明，CRL4 E3 连接酶在监督关键细胞复合物的组装方面具有以前未知的作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c413/9929631/5df1fc7b12b9/EMBJ-42-e112253-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c413/9929631/5b2da53b5249/EMBJ-42-e112253-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c413/9929631/53d565778ac4/EMBJ-42-e112253-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c413/9929631/6acb05d2bf5e/EMBJ-42-e112253-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c413/9929631/694d6e9b72e0/EMBJ-42-e112253-g011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c413/9929631/cd2acd23fffd/EMBJ-42-e112253-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c413/9929631/b6c350cde9cb/EMBJ-42-e112253-g012.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c413/9929631/9c4ef212fef6/EMBJ-42-e112253-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c413/9929631/a04650fcfdc4/EMBJ-42-e112253-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c413/9929631/c6bda8b9fa05/EMBJ-42-e112253-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c413/9929631/5df1fc7b12b9/EMBJ-42-e112253-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c413/9929631/5b2da53b5249/EMBJ-42-e112253-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c413/9929631/53d565778ac4/EMBJ-42-e112253-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c413/9929631/6acb05d2bf5e/EMBJ-42-e112253-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c413/9929631/694d6e9b72e0/EMBJ-42-e112253-g011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c413/9929631/cd2acd23fffd/EMBJ-42-e112253-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c413/9929631/b6c350cde9cb/EMBJ-42-e112253-g012.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c413/9929631/9c4ef212fef6/EMBJ-42-e112253-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c413/9929631/a04650fcfdc4/EMBJ-42-e112253-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c413/9929631/c6bda8b9fa05/EMBJ-42-e112253-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c413/9929631/5df1fc7b12b9/EMBJ-42-e112253-g007.jpg

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2
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Mol Cell. 2022 Apr 21;82(8):1439-1450. doi: 10.1016/j.molcel.2022.02.029. Epub 2022 Mar 21.
3
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Nat Commun. 2024 Aug 21;15(1):7169. doi: 10.1038/s41467-024-51286-w.
4
Mechanism of Ψ-Pro/C-degron recognition by the CRL2 ubiquitin ligase.CRL2 泛素连接酶识别 Ψ-Pro/C-degron 的机制。
Nat Commun. 2024 Apr 26;15(1):3558. doi: 10.1038/s41467-024-47890-5.
5
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6
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7
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