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Molecular basis of β-arrestin coupling to the metabotropic glutamate receptor mGlu3
IF 14.8 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Nature chemical biology
Pub Date : 2025-03-06 DOI: 10.1038/s41589-025-01858-8
Tianlei Wen, Mei Du, Yue Lu, Nan Jia, Xuhang Lu, Ning Liu, Shenghai Chang, Xing Zhang, Yuequan Shen, Xue Yang

β-Arrestins (βarrs) mediate the desensitization and internalization of activated G-protein-coupled receptors (GPCRs). The molecular mechanism by which dimeric family C GPCR members recruit arrestins remains elusive. Here we report two structures of metabotropic glutamate receptor subtype 3 (mGlu3) coupled to βarr1, with stoichiometries of 2:1 and 2:2. The l-glutamate-bound mGlu3 dimer adopts an inactive state, with both Venus flytrap domains closed, engaging βarr1 either asymmetrically or symmetrically. The transmembrane domain of the mGlu3 protomer interacts with βarr1 through a binding pocket formed by three intracellular loops and an ordered C-terminal region. Three phosphorylation sites (pS857, pS859 and pT860) on the C-terminal tail of mGlu3 engage the N domain of βarr1. βarr1 stabilizes mGlu3 in an inactive conformation, characterized by a TM3/TM4–TM3/TM4 dimeric interface, previously observed in the negative allosteric modulator-bound structure of mGlu3. Our findings provide important insights into βarr-mediated inactivation of family C GPCRs.

β-阿司匹林（βarrs）介导活化的 G 蛋白偶联受体（GPCRs）的脱敏和内化。二聚体 C 族 GPCR 成员招募捕获素的分子机制仍未确定。在这里，我们报告了与 βarr1 相耦合的代谢谷氨酸受体亚型 3（mGlu3）的两种结构，其比例分别为 2:1 和 2:2。与 l-谷氨酸结合的 mGlu3 二聚体处于非活性状态，两个金星捕蝇草结构域都关闭，以非对称或对称的方式与 βarr1 结合。mGlu3 原体的跨膜结构域通过由三个胞内环和一个有序的 C 端区域形成的结合袋与βarr1 相互作用。mGlu3 C 端尾部的三个磷酸化位点（pS857、pS859 和 pT860）与 βarr1 的 N 结构域结合。βarr1 使 mGlu3 稳定在非活性构象中，其特征是 TM3/TM4-TM3/TM4 二聚体界面，这是在 mGlu3 的负异位调节剂结合结构中观察到的。我们的发现为βarr介导的 C 族 GPCR 失活提供了重要的见解。
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引用次数: 0
RAS signaling gets granular
IF 14.8 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Nature chemical biology
Pub Date : 2025-03-04 DOI: 10.1038/s41589-025-01851-1
Hugo Lavoie, Marc Therrien
A new study reveals that the RAF isoform ARAF uniquely forms solid-like granules at the cell membrane that have a key role in regulating RAS activation levels and contribute to drug resistance.
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引用次数: 0
The last piece in fucosylation
IF 14.8 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Nature chemical biology
Pub Date : 2025-03-03 DOI: 10.1038/s41589-025-01850-2
Yasuhiko Kizuka
O-fucosylation, a type of protein glycosylation, uniquely occurs on specific protein domains, including the EGF domain in Notch. FUT10 and FUT11, enigmatic fucosyltransferases with weak or unknown activity, have now been identified as protein O-fucosyltransferases that target the EMI domain.
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引用次数: 0
Publisher Correction: Visualizing drug effects over time in live animals using optical pharmacodynamics
IF 14.8 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Nature chemical biology
Pub Date : 2025-02-26 DOI: 10.1038/s41589-025-01865-9

Correction to: Nature Chemical Biology https://doi.org/10.1038/s41589-025-01847-x, published online 14 February 2025.

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引用次数: 0
Guiding generative AI
IF 12.9 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Nature chemical biology
Pub Date : 2025-02-25 DOI: 10.1038/s41589-025-01854-y
Russell Johnson
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引用次数: 0
Turning down the heat
IF 12.9 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Nature chemical biology
Pub Date : 2025-02-25 DOI: 10.1038/s41589-025-01855-x
Grant Miura
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引用次数: 0
Small molecules deliver big
IF 12.9 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Nature chemical biology
Pub Date : 2025-02-25 DOI: 10.1038/s41589-025-01856-w
Gene Chong
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引用次数: 0
Quantitative chemoproteomics reveals dopamine’s protective modification of Tau
IF 14.8 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Nature chemical biology
Pub Date : 2025-02-20 DOI: 10.1038/s41589-025-01849-9
Qianwen Wang, Zhengtao Liu, Youjia Wang, Yuan Liu, Ying Chen, Shengnan Zhang, Wen Zeng, Dan Li, Fan Yang, Zhuohao He, Weidi Xiao, Cong Liu, Chu Wang

Dopamine (DA) is one of the most important neurotransmitters. Its oxidation leads to electrophilic quinone, which covalently modifies nucleophilic residues in proteins, resulting in ‘dopamination’. Individual dopaminated proteins have been studied, most of which were functionally damaged by dopamination. Here, we developed a quantitative chemoproteomic strategy to site-specifically measure proteins’ dopamination. More than 6,000 dopamination sites were quantified. Half-maximal inhibitory concentration values for 63 hypersensitive sites were measured. Among them, hypersensitive dopamination of two cysteines in microtubule-associated protein Tau was biochemically validated and functionally characterized to prevent Tau’s amyloid fibrillation and promote Tau-mediated assembly of microtubules. In addition, endogenous dopamination of Tau in mouse brain was detected through targeted mass spectrometry analysis. Our study not only provides a global portrait of dopamination but also discovers a protective role of DA in regulating the function of Tau, which will enhance our understanding of the physiological and pathological functions of DA in human brain.

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引用次数: 0
Tracking E2-specific substrates
IF 14.8 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Nature chemical biology
Pub Date : 2025-02-19 DOI: 10.1038/s41589-025-01848-w
Hannah B. L. Jones, Andreas Damianou, Benedikt M. Kessler
Advanced E2-modified ubiquitin probes enable investigation of E2-selective ubiquitination in cells and the discovery of tyrosine ubiquitination as a modification occurring in a UBE2D3-specific manner.
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引用次数: 0
The small molecule Ebio3 inactivates the KCNQ2 channel without blocking the pore
IF 14.8 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Nature chemical biology
Pub Date : 2025-02-19 DOI: 10.1038/s41589-025-01853-z
The small molecule Ebio3 inactivates the ‘non-inactivating’ potassium channel KCNQ2. This inhibition occurs by a unique ‘squeeze-to-inhibit’ mechanism, rather than by blocking the channel pore as most KCNQ2 inhibitors do, offering a new mechanism for modulating voltage-gated ion channels with implications for drug discovery.
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引用次数: 0
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