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Molecular basis for ubiquitin ligase CRL2FEM1C-mediated recognition of C-degron.

泛素连接酶CRL2FEM1C-mediated识别C-degron的分子基础。

  • 影响因子:9.33
  • DOI:10.1038/s41589-020-00703-4
  • 作者列表:"Yan X","Wang X","Li Y","Zhou M","Li Y","Song L","Mi W","Min J","Dong C
  • 发表时间:2021-03-01
Abstract

:Proteome integrity depends on the ubiquitin-proteasome system to degrade unwanted or abnormal proteins. In addition to the N-degrons, C-terminal residues of proteins can also serve as degradation signals (C-degrons) that are recognized by specific cullin-RING ubiquitin ligases (CRLs) for proteasomal degradation. FEM1C is a CRL2 substrate receptor that targets the C-terminal arginine degron (Arg/C-degron), but the molecular mechanism of substrate recognition remains largely elusive. Here, we present crystal structures of FEM1C in complex with Arg/C-degron and show that FEM1C utilizes a semi-open binding pocket to capture the C-terminal arginine and that the extreme C-terminal arginine is the major structural determinant in recognition by FEM1C. Together with biochemical and mutagenesis studies, we provide a framework for understanding molecular recognition of the Arg/C-degron by the FEM family of proteins.

摘要

: 蛋白质组完整性依赖于泛素-蛋白酶体系统来降解不需要的或异常的蛋白质。除了N-degrons之外,蛋白质的C-末端残基还可以作为降解信号 (C-degrons),其被蛋白酶体降解的特异性库林-环泛素连接酶 (crl) 识别。FEM1C是CRL2底物受体,其靶向C-末端精氨酸degron (Arg/C-degron),但底物识别的分子机制仍然很难捉摸。在这里,我们提出了FEM1C与Arg/C-degron复合物的晶体结构,并表明FEM1C利用半开放的结合袋捕获C末端精氨酸,极端C末端精氨酸是FEM1C识别的主要结构决定因素。与生物化学和诱变研究一起,我们提供了一个框架,用于理解蛋白质的FEM家族对Arg/C-degron的分子识别。

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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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