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Molecular basis for arginine C-terminal degron recognition by Cul2FEM1 E3 ligase.

Cul2FEM1 E3连接酶识别精氨酸C端degron的分子基础。

  • 影响因子:9.33
  • DOI:10.1038/s41589-020-00704-3
  • 作者列表:"Chen X","Liao S","Makaros Y","Guo Q","Zhu Z","Krizelman R","Dahan K","Tu X","Yao X","Koren I","Xu C
  • 发表时间:2021-03-01
Abstract

:Degrons are elements within protein substrates that mediate the interaction with specific degradation machineries to control proteolysis. Recently, a few classes of C-terminal degrons (C-degrons) that are recognized by dedicated cullin-RING ligases (CRLs) have been identified. Specifically, CRL2 using the related substrate adapters FEM1A/B/C was found to recognize C degrons ending with arginine (Arg/C-degron). Here, we uncover the molecular mechanism of Arg/C-degron recognition by solving a subset of structures of FEM1 proteins in complex with Arg/C-degron-bearing substrates. Our structural research, complemented by binding assays and global protein stability (GPS) analyses, demonstrates that FEM1A/C and FEM1B selectively target distinct classes of Arg/C-degrons. Overall, our study not only sheds light on the molecular mechanism underlying Arg/C-degron recognition for precise control of substrate turnover, but also provides valuable information for development of chemical probes for selectively regulating proteostasis.

摘要

: Degrons是蛋白质底物中的元件,其介导与特定降解机制的相互作用以控制蛋白水解。最近,已经鉴定了由专用的cullin-环连接酶 (crl) 识别的几类C-末端degrons (C-degrons)。具体地,发现使用相关基底适配器FEM1A/B/C的CRL2识别以精氨酸 (Arg/C-degron) 结束的C degrons。在这里,我们通过求解与Arg/C-degron-承载底物复合的FEM1蛋白的结构子集来揭示Arg/C-degron识别的分子机制。我们的结构研究,辅以结合测定和全局蛋白稳定性 (GPS) 分析,证明FEM1A/C和FEM1B选择性靶向不同类别的Arg/C-degrons。总的来说,我们的研究不仅揭示了Arg/C-degron识别精确控制底物周转的分子机制,而且为开发选择性调节蛋白沉积的化学探针提供了有价值的信息。

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影响因子:2.06
发表时间:2021-02-01
DOI:10.1007/s11033-021-06155-w
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发表时间:2021-02-01
DOI:10.1080/14656566.2020.1814255
作者列表:["Sawada H","Oeda T","Kohsaka M","Tomita S","Umemura A","Park K","Yamamoto K","Kiyohara K"]

METHODS:BACKGROUND:Cholinergic neurotransmission regulates neuroinflammation in Parkinson disease (PD). RESEARCH DESIGN AND METHODS:The authors conducted a delayed-start study of donepezil for cognitive decline in non-demented PD patients. The study consisted of a 96-week randomized placebo-controlled double-blind phase 1, followed by a 24-week donepezil extension phase 2. The primary outcome measure was a change in the Mini-Mental State Examination (MMSE) at week 120. RESULTS:A total of 98 patients were randomly allocated to the early-start (donepezil-to-donepezil) and delayed-start (placebo-to-donepezil) groups. Mean (SD) of the baseline MMSE was 27.6 (2.0) and 28.0 (2.1), respectively. MMSE change at week 120 was better in the early-start group than in the delayed-start group, but the difference was not significant. The MMSE declined in apolipoprotein ε4 carriers, but not in non-carriers, and the factor interaction (intervention × ε4 genotype) was highly significant (P < 0.001). Analyzed with the interaction, the difference was significant (group difference 1.95 [0.33 to 3.57], P = 0.018). The MMSE decline slope in phase 1 was significantly better in the early-start group than in the delayed-start group (P = 0.048). CONCLUSIONS:Cognitive function deteriorated in ε4 carriers, but not in non-carriers, and early-start donepezil may postpone cognitive decline in the former.

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发表时间:2021-03-24
DOI:10.1007/s11033-021-06299-9
作者列表:["Louvrier A","Terranova L","Meyer C","Meyer F","Euvrard E","Kroemer M","Rolin G"]

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