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A team of chaperones play to win in the bacterial periplasm 在细菌的外质中,一队陪护人员玩得不亦乐乎。
IF 11.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-01 DOI: 10.1016/j.tibs.2024.03.015

The survival and virulence of Gram-negative bacteria require proper biogenesis and maintenance of the outer membrane (OM), which is densely packed with β-barrel OM proteins (OMPs). Before reaching the OM, precursor unfolded OMPs (uOMPs) must cross the whole cell envelope. A network of periplasmic chaperones and proteases maintains unfolded but folding-competent conformations of these membrane proteins in the aqueous periplasm while simultaneously preventing off-pathway aggregation. These periplasmic proteins utilize different strategies, including conformational heterogeneity, oligomerization, multivalency, and kinetic partitioning, to perform and regulate their functions. Redundant and unique characteristics of the individual periplasmic players synergize to create a protein quality control team capable responding to changing environmental stresses.

革兰氏阴性细菌的生存和毒力需要外膜(OM)的正常生物生成和维持,外膜上密布着β-管状 OM 蛋白(OMPs)。在到达外膜之前,未折叠的前体外膜蛋白(uOMPs)必须穿过整个细胞包膜。细胞质周围的伴侣蛋白和蛋白酶网络可将这些膜蛋白未折叠但具有折叠能力的构象保持在水性细胞质周围,同时防止其偏离途径聚集。这些周质蛋白利用不同的策略(包括构象异质性、寡聚化、多价性和动力学分区)来执行和调节它们的功能。各个外质蛋白的冗余和独特特性协同作用,形成了一个蛋白质质量控制团队,能够应对不断变化的环境压力。
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引用次数: 0
Assembling a Hippo: the evolutionary emergence of an animal developmental signaling pathway 组装河马:动物发育信号通路的进化过程。
IF 11.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-01 DOI: 10.1016/j.tibs.2024.04.005

Decades of work in developmental genetics has given us a deep mechanistic understanding of the fundamental signaling pathways underlying animal development. However, little is known about how these pathways emerged and changed over evolutionary time. Here, we review our current understanding of the evolutionary emergence of the Hippo pathway, a conserved signaling pathway that regulates tissue size in animals. This pathway has deep evolutionary roots, emerging piece by piece in the unicellular ancestors of animals, with a complete core pathway predating the origin of animals. Recent functional studies in close unicellular relatives of animals and early-branching animals suggest an ancestral function of the Hippo pathway in cytoskeletal regulation, which was subsequently co-opted to regulate proliferation and animal tissue size.

数十年的发育遗传学研究使我们对动物发育的基本信号通路有了深入的机理认识。然而,我们对这些通路是如何随着进化时间的推移而出现和变化的却知之甚少。在这里,我们回顾了我们目前对 Hippo 通路进化出现的理解,这是一条调节动物组织大小的保守信号通路。这条通路有着深厚的进化根基,在动物的单细胞祖先中逐一出现,其完整的核心通路早在动物起源之前就已存在。最近在动物的单细胞近亲和早期分支动物中进行的功能研究表明,Hippo 通路具有细胞骨架调节的祖先功能,后来被用于调节增殖和动物组织的大小。
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引用次数: 0
The YTHDF proteins display distinct cellular functions on m6A-modified RNA YTHDF 蛋白在 m6A 修饰的 RNA 上显示出不同的细胞功能。
IF 11.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-01 DOI: 10.1016/j.tibs.2024.04.001
Zhongyu Zou , Chuan He

YTHDF proteins are main cytoplasmic ‘reader’ proteins of RNA N6-methyladenosine (m6A) methylation in mammals. They are largely responsible for m6A-mediated regulation in the cell cytosol by controlling both mRNA translation and degradation. Recent functional and mechanistic investigations of the YTHDF proteins revealed that these proteins have different functions to enable versatile regulation of the epitranscriptome. Their divergent functions largely originate from their different amino acid sequences in the low-complexity N termini. Consequently, they have different phase separation propensities and possess distinct post-translational modifications (PTMs). Different PTMs, subcellular localizations, and competition among partner proteins have emerged as three major mechanisms that control the functions of these YTHDF proteins. We also summarize recent progress on critical roles of these YTHDF proteins in anticancer immunity and the potential for targeting these proteins for developing new anticancer therapies.

YTHDF 蛋白是哺乳动物体内 RNA N6-甲基腺苷(m6A)甲基化的主要细胞质 "阅读器 "蛋白。它们通过控制 mRNA 的翻译和降解,对细胞胞体中由 m6A 介导的调控负主要责任。最近对 YTHDF 蛋白进行的功能和机理研究发现,这些蛋白具有不同的功能,能够对表转录组进行多功能调控。它们的不同功能主要源于低复杂度 N 端不同的氨基酸序列。因此,它们具有不同的相分离倾向和不同的翻译后修饰(PTM)。不同的 PTM、亚细胞定位以及伙伴蛋白之间的竞争已成为控制这些 YTHDF 蛋白功能的三大机制。我们还总结了这些 YTHDF 蛋白在抗癌免疫中的关键作用的最新进展,以及以这些蛋白为靶点开发新型抗癌疗法的潜力。
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引用次数: 0
Taming AID mutator activity in somatic hypermutation 驯服体细胞超突变中的 AID 突变体活性
IF 11.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-01 DOI: 10.1016/j.tibs.2024.03.011
Yining Qin , Fei-Long Meng

Activation-induced cytidine deaminase (AID) initiates somatic hypermutation (SHM) by introducing base substitutions into antibody genes, a process enabling antibody affinity maturation in immune response. How a mutator is tamed to precisely and safely generate programmed DNA lesions in a physiological process remains unsettled, as its dysregulation drives lymphomagenesis. Recent research has revealed several hidden features of AID-initiated mutagenesis: preferential activity on flexible DNA substrates, restrained activity within chromatin loop domains, unique DNA repair factors to differentially decode AID-caused lesions, and diverse consequences of aberrant deamination. Here, we depict the multifaceted regulation of AID activity with a focus on emerging concepts/factors and discuss their implications for the design of base editors (BEs) that install somatic mutations to correct deleterious genomic variants.

活化诱导胞苷脱氨酶(AID)通过将碱基置换引入抗体基因启动体细胞超突变(SHM),这一过程使免疫反应中的抗体亲和力成熟。如何驯服突变体,使其在生理过程中精确、安全地产生程序性DNA病变,目前仍是一个悬而未决的问题,因为突变体的失调会导致淋巴瘤的发生。最近的研究揭示了 AID 引发诱变的几个隐藏特征:在柔性 DNA 底物上的优先活性、染色质环状结构域内的受限活性、独特的 DNA 修复因子对 AID 引起的病变进行不同的解码,以及异常脱氨的各种后果。在这里,我们描绘了 AID 活性的多方面调控,重点是新出现的概念/因素,并讨论了它们对设计碱基编辑器(BE)的影响,碱基编辑器可以安装体细胞突变来纠正有害的基因组变异。
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引用次数: 0
Hypoxia research, where to now? 缺氧研究,何去何从?
IF 11.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-01 DOI: 10.1016/j.tibs.2024.03.008
Brian M. Ortmann , Cormac T. Taylor , Sonia Rocha

Investigating how cells and organisms sense and respond to O2 levels is essential to our understanding of physiology and pathology. This field has advanced considerably since the discovery of the major transcription factor family, hypoxia-inducible factor (HIF), and the enzymes that control its levels: prolyl hydroxylases (PHDs). However, with its expansion, new complexities have emerged. Herein we highlight three main areas where, in our opinion, the research community could direct some of their attention. These include non-transcriptional roles of HIFs, specificity and O2 sensitivity of 2-oxoglutarate-dependent dioxygenases (2-OGDDs), and new tools and methods to detect O2 concentrations in cells and organs. A greater understanding of these areas would answer big questions and help drive our knowledge of cellular responses to hypoxia forward.

研究细胞和生物体如何感知氧气水平并对其做出反应,对于我们了解生理学和病理学至关重要。自从发现主要转录因子家族--缺氧诱导因子(HIF)和控制其水平的酶:脯氨酰羟化酶(PHDs)以来,这一领域取得了长足的进步。然而,随着其规模的扩大,新的复杂性也随之出现。在此,我们强调三个我们认为研究界可以关注的主要领域。这些领域包括 HIFs 的非转录作用、2-氧代戊二酸依赖性二氧酶(2-OGDDs)的特异性和对氧气的敏感性,以及检测细胞和器官中氧气浓度的新工具和方法。加深对这些领域的了解将解答重大问题,并有助于推动我们对细胞缺氧反应的认识向前发展。
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引用次数: 0
Sortases: structure, mechanism, and implications for protein engineering 排序酶:结构、机制和对蛋白质工程的影响。
IF 11.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-01 DOI: 10.1016/j.tibs.2024.04.003
Jeanine F. Amacher , John M. Antos

Sortase enzymes are critical cysteine transpeptidases on the surface of bacteria that attach proteins to the cell wall and are involved in the construction of bacterial pili. Due to their ability to recognize specific substrates and covalently ligate a range of reaction partners, sortases are widely used in protein engineering applications via sortase-mediated ligation (SML) strategies. In this review, we discuss recent structural studies elucidating key aspects of sortase specificity and the catalytic mechanism. We also highlight select recent applications of SML, including examples where fundamental studies of sortase structure and function have informed the continued development of these enzymes as tools for protein engineering.

分选酶是细菌表面的关键半胱氨酸转肽酶,可将蛋白质附着到细胞壁上,并参与细菌纤毛的构建。由于分选酶具有识别特定底物和共价连接一系列反应伙伴的能力,因此通过分选酶介导的连接(SML)策略,分选酶被广泛应用于蛋白质工程领域。在这篇综述中,我们讨论了最近的结构研究,这些研究阐明了分选酶特异性和催化机理的关键方面。我们还重点介绍了 SML 的一些最新应用,包括分选酶结构和功能的基础研究为这些酶作为蛋白质工程工具的持续发展提供信息的实例。
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引用次数: 0
(G)Patching up mis-splicing in cancer (G)修补癌症中的错误拼接。
IF 11.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-01 DOI: 10.1016/j.tibs.2024.05.001
Maciej Cieśla , Cristian Bellodi

Benbarche, Pineda, Galvis, et al. delineate an essential role for the G-patch motif-containing protein GPATCH8 in mis-splicing associated with cancer-driving mutations of the splicing factor SF3B1. GPATCH8 cooperates with SF3B1 mutants, affecting the splicing machinery. Targeting GPATCH8 reveals therapeutic opportunities for SF3B1 mutant cancers and other splicing-related diseases.

Benbarche、Pineda、Galvis 等人发现,在与剪接因子 SF3B1 的癌症驱动突变相关的错误剪接中,含 G-补丁图案的蛋白质 GPATCH8 扮演着重要角色。 GPATCH8 与 SF3B1 突变体合作,影响剪接机制。针对 GPATCH8 的研究为 SF3B1 突变癌症和其他剪接相关疾病提供了治疗机会。
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引用次数: 0
The physiological relevance of autophagosome morphogenesis 自噬体形态发生的生理意义
IF 11.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-01 DOI: 10.1016/j.tibs.2024.05.002
Oren Shatz , Zvulun Elazar

Autophagy sequesters cytoplasmic portions into autophagosomes. While selective cargo is engulfed by elongation of cup-shaped isolation membranes (IMs), the morphogenesis of non-selective IMs remains elusive. Based on recent observations, we propose a novel model for autophagosome morphogenesis wherein active regulation of the IM rim serves the physiological roles of autophagy.

自噬将细胞质部分封存到自噬体中。选择性货物通过杯状隔离膜(IMs)的伸长被吞噬,而非选择性IMs的形态发生仍然难以捉摸。根据最近的观察结果,我们提出了一种新的自噬体形态发生模型,其中对 IM 边缘的主动调控为自噬的生理作用服务。
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引用次数: 0
Subconductance states add complexity to Piezo1 gating model 亚导状态增加了 Piezo1 门控模型的复杂性。
IF 11.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-01 DOI: 10.1016/j.tibs.2024.05.005
Marie E. Cronin , Jörg Grandl

Piezos are force-gated ion channels that detect and communicate membrane tension to the cell. Recent work from Ullah, Nosyreva, and colleagues characterizes partial channel openings, known as subconductance states, and develops a new gating model of Piezo1 function.

压电离子通道是一种力门控离子通道,能检测膜张力并将其传递给细胞。最近,Ullah、Nosyreva 及其同事的研究工作描述了通道部分开放(称为亚导状态)的特征,并建立了 Piezo1 功能的新门控模型。
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引用次数: 0
CellVis2: a conference on visualizing the molecular cell CellVis2:分子细胞可视化会议
IF 11.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-01 DOI: 10.1016/j.tibs.2024.03.013
Ludovic Autin , David S. Goodsell , Ivan Viola , Arthur Olson

In January 2024, a targeted conference, ‘CellVis2’, was held at Scripps Research in La Jolla, USA, the second in a series designed to explore the promise, practices, roadblocks, and prospects of creating, visualizing, sharing, and communicating physical representations of entire biological cells at scales down to the atom.

2024 年 1 月,一场名为 "CellVis2 "的定向会议在美国拉霍亚的斯克里普斯研究所举行,这是系列会议中的第二次会议,旨在探讨创建、可视化、共享和交流整个生物细胞的物理表示(最小到原子)的前景、实践、障碍和展望。
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引用次数: 0
期刊
Trends in Biochemical Sciences
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