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Protein quality control machinery: regulators of condensate architecture and functionality 蛋白质质量控制机械：冷凝水结构和功能的调节器。
IF 11.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Trends in Biochemical Sciences
Pub Date : 2025-02-01 DOI: 10.1016/j.tibs.2024.12.003
Anitha Rajendran , Carlos A. Castañeda
Protein quality control (PQC) mechanisms including the ubiquitin (Ub)-proteasome system (UPS), autophagy, and chaperone-mediated refolding are essential to maintain protein homeostasis in cells. Recent studies show that these PQC mechanisms are further modulated by biomolecular condensates that sequester PQC components and compartmentalize reactions. Accumulating evidence points towards the PQC machinery playing a pivotal role in regulating the assembly, disassembly, and viscoelastic properties of several condensates. Here, we discuss how the PQC machinery can form their own condensates and also be recruited to known condensates under physiological or stress-induced conditions. We present molecular insights into how the multivalent architecture of polyUb chains, Ub-binding adaptor proteins, and other PQC machinery contribute to condensate assembly, leading to the regulation of downstream PQC outcomes and therapeutic potential.
蛋白质质量控制（PQC）机制包括泛素(Ub)-蛋白酶体系统（UPS）、自噬和伴侣介导的重折叠对于维持细胞中的蛋白质稳态至关重要。最近的研究表明，这些PQC机制被生物分子凝聚物进一步调节，这些凝聚物隔离了PQC成分并使反应区隔化。越来越多的证据表明，PQC机制在调节几种凝析油的组装、拆卸和粘弹性性能方面起着关键作用。在这里，我们讨论了PQC机制如何在生理或应力诱导条件下形成自己的凝聚体并被招募到已知的凝聚体中。我们介绍了多价结构的polyb链、ub结合接头蛋白和其他PQC机制如何促进冷凝物组装，从而导致下游PQC结果的调节和治疗潜力。
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引用次数: 0
Chemical probes for imaging cellular compartmentalization 成像细胞区隔化的化学探针。
IF 11.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Trends in Biochemical Sciences
Pub Date : 2025-02-01 DOI: 10.1016/j.tibs.2024.12.005
Margret H. Bülow , Johannes Broichhagen
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引用次数: 0
Synaptoneurolipidomics: lipidomics in the study of synaptic function 突触神经脂组学：研究突触功能的脂组学。
IF 11.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Trends in Biochemical Sciences
Pub Date : 2025-02-01 DOI: 10.1016/j.tibs.2024.12.004
Robert Ahrends , Shane R. Ellis , Steven H.L. Verhelst , Michael R. Kreutz
The brain is an exceptionally lipid-rich organ with a very complex lipid composition. Lipids are central in several neuronal processes, including membrane formation and fusion, myelin packing, and lipid-mediated signal transmission. Lipid diversity is associated with the evolution of higher cognitive abilities in primates, is affected by neuronal activity, and is instrumental for synaptic plasticity, illustrating that lipids are not static components of synaptic membranes. Several lines of evidence suggest that the lipid composition of synapses is unique and distinct from other neuronal subcompartments. Here, we delve into the nascent field of synaptoneurolipidomics, offering an overview of current knowledge on the lipid composition of synaptic junctions and technological advances that will allow us to study the impact on synaptic function.
大脑是一个异常富含脂质的器官，具有非常复杂的脂质组成。脂质在一些神经元过程中起着中心作用，包括膜的形成和融合、髓磷脂的堆积和脂质介导的信号传递。脂质多样性与灵长类动物高级认知能力的进化有关，受神经元活动的影响，并有助于突触的可塑性，这表明脂质不是突触膜的静态成分。一些证据表明，突触的脂质组成是独特的，与其他神经元亚室不同。在这里，我们将深入研究突触神经脂组学这一新兴领域，概述当前关于突触连接脂质组成的知识和技术进步，这将使我们能够研究对突触功能的影响。
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引用次数: 0
Subscription and Copyright Information
IF 11.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Trends in Biochemical Sciences
Pub Date : 2025-02-01 DOI: 10.1016/S0968-0004(25)00014-3
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引用次数: 0
Textbook oxidative phosphorylation needs to be rewritten 教科书中的氧化磷酸化需要重写。
IF 11.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Trends in Biochemical Sciences
Pub Date : 2025-02-01 DOI: 10.1016/j.tibs.2024.11.002
Alicia J. Kowaltowski , Fernando Abdulkader
Oxidative phosphorylation (OxPhos) is the energy-transfer process that generates most of our ATP, fueled by proton and electrical gradients across the inner mitochondrial membrane. A new surprising finding by Hernansanz-Agustín et al. demonstrates that between one-third and half of this gradient is attributable to Na+, transported in exchange for protons within complex I.
氧化磷酸化（OxPhos）是产生大部分 ATP 的能量转移过程，其动力来自线粒体内膜上的质子和电梯度。埃尔南桑斯-阿古斯丁（Hernansanz-Agustín）等人的一项新的惊人发现表明，这种梯度的三分之一到一半可归因于Na+，它在复合体 I 中被输送以交换质子。
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引用次数: 0
Advisory Board and Contents
IF 11.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Trends in Biochemical Sciences
Pub Date : 2025-02-01 DOI: 10.1016/S0968-0004(25)00011-8
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引用次数: 0
Chaperone-dependent and chaperone-independent functions of carboxylate clamp tetratricopeptide repeat (CC-TPR) proteins 羧酸夹紧四肽重复（CC-TPR）蛋白的伴侣依赖性和伴侣非依赖性功能。
IF 11.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Trends in Biochemical Sciences
Pub Date : 2025-02-01 DOI: 10.1016/j.tibs.2024.11.004
Saugat Pokhrel , Shweta Devi , Jason E. Gestwicki
The molecular chaperones HSP70 and HSP90 play key roles in proteostasis by acting as adapters; they bind to a 'client' protein, often with the assistance of cochaperones, and then recruit additional cochaperones that promote specific fates (e.g., folding or degradation). One family of cochaperones contains a region termed the tetratricopeptide repeat with carboxylate clamps (CC-TPRs) domain. These domains bind to an EEVD motif at the C-termini of cytoplasmic HSP70 and HSP90 proteins, bringing them into proximity to chaperone-bound clients. It has recently become clear that CC-TPR proteins also bind to 'EEVD-like' motifs in non-chaperone proteins, circumventing the need for HSP70s or HSP90s. We provide an overview of the chaperone-dependent and -independent roles of CC-TPR proteins and discuss how, together, they shape proteostasis.
分子伴侣蛋白HSP70和HSP90作为转接器在蛋白质静止中起关键作用；它们通常在伴侣的帮助下与“客户”蛋白结合，然后招募额外的伴侣来促进特定的命运（例如折叠或降解）。一个家族的伴侣包含一个区域称为羧酸夹（CC-TPRs）结构域的四肽重复。这些结构域与细胞质HSP70和HSP90蛋白的c端EEVD基序结合，使它们接近伴侣结合的客户端。最近已经清楚的是，CC-TPR蛋白也与非伴侣蛋白中的“eevd样”基序结合，绕过了对hsp70或hsp90的需要。我们概述了CC-TPR蛋白的伴侣依赖性和非伴侣依赖性作用，并讨论了它们如何共同塑造蛋白质稳态。
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引用次数: 0
Exploring protein conformations with limited proteolysis coupled to mass spectrometry 用有限的蛋白水解结合质谱法探索蛋白质构象。
IF 11.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Trends in Biochemical Sciences
Pub Date : 2025-02-01 DOI: 10.1016/j.tibs.2024.11.005
Chloé Van Leene , Laura Van Moortel , Karolien De Bosscher , Kris Gevaert
Limited proteolysis coupled to mass spectrometry (LiP-MS) has emerged as a powerful proteomic tool for studying protein conformations. Since its introduction in 2014, LiP-MS has expanded its scope to explore complex biological systems and shed light on disease mechanisms, and has been used for protein drug research. This review discusses the evolution of the technique, recent technical advances, including enhanced protocols and integration of machine learning, and diverse applications across various experimental models. Despite its achievements, challenges in protein extraction and conformotypic peptide identification remain. Ongoing methodological refinements will be crucial to overcome these challenges and enhance the capabilities of the technique. However, LiP-MS offers significant potential for future discoveries in structural proteomics and medical research.
有限蛋白水解耦合质谱（LiP-MS）已成为研究蛋白质构象的强大蛋白质组学工具。自2014年推出以来，LiP-MS已将其范围扩大到探索复杂生物系统和揭示疾病机制，并已用于蛋白质药物研究。本文讨论了该技术的发展，最近的技术进步，包括增强的协议和机器学习的集成，以及各种实验模型的不同应用。尽管取得了一定的成就，但在蛋白质提取和构象肽鉴定方面仍然存在挑战。正在进行的方法改进将是克服这些挑战和提高技术能力的关键。然而，LiP-MS为未来结构蛋白质组学和医学研究的发现提供了巨大的潜力。
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引用次数: 0
Routes to molecular glue degrader discovery 发现分子胶水降解剂的途径。
IF 11.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Trends in Biochemical Sciences
Pub Date : 2025-02-01 DOI: 10.1016/j.tibs.2024.12.006
Yanfen Liu , Jieyun Bai , Dong Li , Yong Cang
Molecular glue degraders (MGDs) represent a unique class of targeted protein degradation (TPD) modalities. By facilitating protein–protein interactions between E3 ubiquitin ligases and neo-substrates, MGDs offer a novel approach to target previously undruggable or insufficiently drugged disease-causing proteins. Here, we present an overview of recently reported MGDs, highlighting their diverse mechanisms, and we discuss mechanism-based strategies to discover new MGDs and neo-substrates. These strategies include repurposing existing E3 ubiquitin ligase-targeting ligands, screening for novel binders to proteins of interest, and leveraging functional genomics and quantitative proteomics to probe the MGD mechanism of action. Despite their historically serendipitous discovery, MGDs are on their way to being rationally designed to deplete undesired proteins by purposely altering the evolutionarily conserved ligase:substrate interactions.
分子胶降解剂（MGDs）代表了一类独特的靶向蛋白降解（TPD）模式。通过促进E3泛素连接酶和新底物之间的蛋白相互作用，MGDs提供了一种新的方法来靶向以前不可药物或药物不足的致病蛋白。在这里，我们概述了最近报道的MGDs，强调了它们的不同机制，并讨论了发现新的MGDs和新底物的基于机制的策略。这些策略包括重新利用现有的E3泛素连接酶靶向配体，筛选感兴趣的蛋白质的新结合物，以及利用功能基因组学和定量蛋白质组学来探索MGD的作用机制。尽管它们在历史上是偶然发现的，但MGDs正在被合理地设计，通过有意改变进化上保守的连接酶：底物相互作用来消耗不需要的蛋白质。
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引用次数: 0
Crabtree effect in yeast: a phosphate tug-of-war between fermentation and respiration 酵母中的Crabtree效应：发酵与呼吸之间的磷酸盐拔河。
IF 11.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Trends in Biochemical Sciences
Pub Date : 2025-02-01 DOI: 10.1016/j.tibs.2024.12.001
Ananda Krishnan Manoj , Aswathy Valsalakumari Saradanandan , Vijay Jayaraman
The Crabtree effect in yeast, where cells prefer fermentation over respiration in high -glucose environments, is associated with mitochondrial repression, but the molecular mechanisms were previously unclear. Recently, Vengayil et al. revealed that knocking out the ubp3 gene, encoding a deubiquitinase enzyme, mitigates the Crabtree effect by increasing mitochondrial phosphate levels.
酵母中的Crabtree效应与线粒体抑制有关，酵母细胞在高葡萄糖环境中更喜欢发酵而不是呼吸作用，但分子机制此前尚不清楚。最近，Vengayil等人发现敲除编码去泛素酶的ubp3基因可以通过增加线粒体磷酸盐水平来减轻Crabtree效应。
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