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The Inseparable Relationship Between Cholesterol and Hedgehog Signaling. 胆固醇与刺猬信号之间密不可分的关系
IF 12.1 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2023-06-20 Epub Date: 2023-03-31 DOI: 10.1146/annurev-biochem-052521-040313
Christian Siebold, Rajat Rohatgi

Ligands of the Hedgehog (HH) pathway are paracrine signaling molecules that coordinate tissue development in metazoans. A remarkable feature of HH signaling is the repeated use of cholesterol in steps spanning ligand biogenesis, secretion, dispersal, and reception on target cells. A cholesterol molecule covalently attached to HH ligands is used as a molecular baton by transfer proteins to guide their secretion, spread, and reception. On target cells, a signaling circuit composed of a cholesterol transporter and sensor regulates transmission of HH signals across the plasma membrane to the cytoplasm. The repeated use of cholesterol in signaling supports the view that the HH pathway likely evolved by coopting ancient systems to regulate the abundance or organization of sterol-like lipids in membranes.

刺猬(HH)通路的配体是一种旁分泌信号分子,可协调类脊椎动物的组织发育。HH 信号传导的一个显著特点是在配体的生物生成、分泌、散布和靶细胞接收等步骤中反复使用胆固醇。共价连接到 HH 配体上的胆固醇分子被转移蛋白用作分子指挥棒,引导配体的分泌、扩散和接收。在靶细胞上,由胆固醇转运体和传感器组成的信号回路调节 HH 信号穿过质膜向细胞质的传递。胆固醇在信号传递中的反复使用支持了这样一种观点,即 HH 通路很可能是通过共用古代系统来调节膜中类固醇脂质的丰度或组织而进化而来的。
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引用次数: 0
The Activation Mechanism of the Insulin Receptor: A Structural Perspective. 胰岛素受体的激活机制:一个结构视角。
IF 16.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2023-06-20 DOI: 10.1146/annurev-biochem-052521-033250
Eunhee Choi, Xiao-Chen Bai

The insulin receptor (IR) is a type II receptor tyrosine kinase that plays essential roles in metabolism, growth, and proliferation. Dysregulation of IR signaling is linked to many human diseases, such as diabetes and cancers. The resolution revolution in cryo-electron microscopy has led to the determination of several structures of IR with different numbers of bound insulin molecules in recent years, which have tremendously improved our understanding of how IR is activated by insulin. Here, we review the insulin-induced activation mechanism of IR, including (a) the detailed binding modes and functions of insulin at site 1 and site 2 and (b) the insulin-induced structural transitions that are required for IR activation. We highlight several other key aspects of the activation and regulation of IR signaling and discuss the remaining gaps in our understanding of the IR activation mechanism and potential avenues of future research.

胰岛素受体(IR)是一种II型受体酪氨酸激酶,在代谢、生长和增殖中起重要作用。IR信号的失调与许多人类疾病有关,如糖尿病和癌症。近年来,冷冻电子显微镜的分辨率革命导致了几种具有不同数量的胰岛素结合分子的IR结构的确定,这极大地提高了我们对胰岛素如何激活IR的理解。在这里,我们回顾了胰岛素诱导的IR激活机制,包括(a)胰岛素在位点1和位点2的详细结合模式和功能,以及(b)胰岛素诱导的IR激活所需的结构转变。我们强调了IR信号的激活和调节的其他几个关键方面,并讨论了我们对IR激活机制和未来研究的潜在途径的理解中的剩余空白。
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引用次数: 6
The Proteins of mRNA Modification: Writers, Readers, and Erasers. mRNA修饰的蛋白质:写入器,读取器和擦除器。
IF 16.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2023-06-20 DOI: 10.1146/annurev-biochem-052521-035330
Mathieu N Flamand, Matthew Tegowski, Kate D Meyer

Over the past decade, mRNA modifications have emerged as important regulators of gene expression control in cells. Fueled in large part by the development of tools for detecting RNA modifications transcriptome wide, researchers have uncovered a diverse epitranscriptome that serves as an additional layer of gene regulation beyond simple RNA sequence. Here, we review the proteins that write, read, and erase these marks, with a particular focus on the most abundant internal modification, N6-methyladenosine (m6A). We first describe the discovery of the key enzymes that deposit and remove m6A and other modifications and discuss how our understanding of these proteins has shaped our views of modification dynamics. We then review current models for the function of m6A reader proteins and how our knowledge of these proteins has evolved. Finally, we highlight important future directions for the field and discuss key questions that remain unanswered.

在过去的十年中,mRNA修饰已成为细胞中基因表达控制的重要调节因子。在很大程度上,由于广泛检测RNA修饰转录组的工具的发展,研究人员发现了一种多样化的表转录组,它可以作为简单RNA序列之外的基因调控层。在这里,我们回顾了编写、读取和擦除这些标记的蛋白质,特别关注最丰富的内部修饰,n6 -甲基腺苷(m6A)。我们首先描述了沉积和去除m6A和其他修饰的关键酶的发现,并讨论了我们对这些蛋白质的理解如何影响了我们对修饰动力学的看法。然后,我们回顾了m6A读取器蛋白功能的当前模型,以及我们对这些蛋白的认识是如何演变的。最后,我们强调了该领域的重要未来方向,并讨论了尚未解决的关键问题。
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引用次数: 14
Polyamines in Parkinson's Disease: Balancing Between Neurotoxicity and Neuroprotection. 帕金森病中的多胺:神经毒性和神经保护之间的平衡。
IF 16.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2023-06-20 DOI: 10.1146/annurev-biochem-071322-021330
Stephanie Vrijsen, Marine Houdou, Ana Cascalho, Jan Eggermont, Peter Vangheluwe

The polyamines putrescine, spermidine, and spermine are abundant polycations of vital importance in mammalian cells. Their cellular levels are tightly regulated by degradation and synthesis, as well as by uptake and export. Here, we discuss the delicate balance between the neuroprotective and neurotoxic effects of polyamines in the context of Parkinson's disease (PD). Polyamine levels decline with aging and are altered in patients with PD, whereas recent mechanistic studies on ATP13A2 (PARK9) demonstrated a driving role of a disturbed polyamine homeostasis in PD. Polyamines affect pathways in PD pathogenesis, such as α-synuclein aggregation, and influence PD-related processes like autophagy, heavy metal toxicity, oxidative stress, neuroinflammation, and lysosomal/mitochondrial dysfunction. We formulate outstanding research questions regarding the role of polyamines in PD, their potential as PD biomarkers, and possible therapeutic strategies for PD targeting polyamine homeostasis.

多胺腐胺、亚精胺和精胺是哺乳动物细胞中非常重要的多聚体。它们的细胞水平受到降解和合成以及吸收和输出的严格调节。在这里,我们讨论在帕金森病(PD)的背景下多胺的神经保护和神经毒性作用之间的微妙平衡。多胺水平随着年龄的增长而下降,PD患者的多胺水平也会发生改变,而最近对ATP13A2 (PARK9)的机制研究表明,多胺稳态紊乱在PD中起着驱动作用。多胺影响PD发病途径,如α-突触核蛋白聚集,并影响PD相关过程,如自噬、重金属毒性、氧化应激、神经炎症和溶酶体/线粒体功能障碍。我们就多胺在帕金森病中的作用、它们作为帕金森病生物标志物的潜力以及针对多胺稳态的帕金森病可能的治疗策略提出了突出的研究问题。
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引用次数: 4
Translation and mRNA Stability Control. 翻译和 mRNA 稳定性控制
IF 12.1 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2023-06-20 Epub Date: 2023-03-31 DOI: 10.1146/annurev-biochem-052621-091808
Qiushuang Wu, Ariel A Bazzini

Messenger RNA (mRNA) stability and translational efficiency are two crucial aspects of the post-transcriptional process that profoundly impact protein production in a cell. While it is widely known that ribosomes produce proteins, studies during the past decade have surprisingly revealed that ribosomes also control mRNA stability in a codon-dependent manner, a process referred to as codon optimality. Therefore, codons, the three-nucleotide words read by the ribosome, have a potent effect on mRNA stability and provide cis-regulatory information that extends beyond the amino acids they encode. While the codon optimality molecular mechanism is still unclear, the translation elongation rate appears to trigger mRNA decay. Thus, transfer RNAs emerge as potential master gene regulators affecting mRNA stability. Furthermore, while few factors related to codon optimality have been identified in yeast, the orthologous genes in vertebrates do not necessary share the same functions. Here, we discuss codon optimality findings and gene regulation layers related to codon composition in different eukaryotic species.

信使 RNA(mRNA)的稳定性和翻译效率是转录后过程的两个关键方面,对细胞中蛋白质的产生有着深远的影响。众所周知,核糖体产生蛋白质,但过去十年的研究却令人惊讶地发现,核糖体还以依赖密码子的方式控制 mRNA 的稳定性,这一过程被称为密码子优化。因此,密码子,即核糖体读取的三个核苷酸单词,对 mRNA 的稳定性具有强大的影响,并提供超越其编码的氨基酸的顺式调控信息。虽然密码子优化的分子机制尚不清楚,但翻译延伸率似乎会引发 mRNA 的衰变。因此,转移核糖核酸成为影响 mRNA 稳定性的潜在主基因调控因子。此外,虽然在酵母中发现了一些与密码子优化相关的因子,但脊椎动物中的同源基因并不一定具有相同的功能。在这里,我们将讨论不同真核生物物种中与密码子组成相关的密码子优化发现和基因调控层。
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引用次数: 0
Managing the Steady State Chromatin Landscape by Nucleosome Dynamics. 通过核糖体动力学管理稳态染色质景观
IF 12.1 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2022-06-21 Epub Date: 2022-03-18 DOI: 10.1146/annurev-biochem-032620-104508
Kami Ahmad, Steven Henikoff, Srinivas Ramachandran

Gene regulation arises out of dynamic competition between nucleosomes, transcription factors, and other chromatin proteins for the opportunity to bind genomic DNA. The timescales of nucleosome assembly and binding of factors to DNA determine the outcomes of this competition at any given locus. Here, we review how these properties of chromatin proteins and the interplay between the dynamics of different factors are critical for gene regulation. We discuss how molecular structures of large chromatin-associated complexes, kinetic measurements, and high resolution mapping of protein-DNA complexes in vivo set the boundary conditions for chromatin dynamics, leading to models of how the steady state behaviors of regulatory elements arise.

基因调控源于核小体、转录因子和其他染色质蛋白之间为争夺与基因组 DNA 结合的机会而展开的动态竞争。核小体组装和因子与 DNA 结合的时间尺度决定了任何给定基因座上这种竞争的结果。在这里,我们将回顾染色质蛋白的这些特性以及不同因子动态之间的相互作用是如何对基因调控起到关键作用的。我们将讨论大型染色质相关复合物的分子结构、动力学测量以及体内蛋白质-DNA 复合物的高分辨率图谱如何为染色质动力学设定边界条件,从而建立调控因子稳态行为的模型。
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引用次数: 0
Structure and Mechanism of the Lipid Flippase MurJ. 脂质翻转酶murp的结构与机制
IF 16.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2022-06-21 DOI: 10.1146/annurev-biochem-040320-105145
Alvin C Y Kuk, Aili Hao, Seok-Yong Lee

Biosynthesis of many important polysaccharides (including peptidoglycan, lipopolysaccharide, and N-linked glycans) necessitates the transport of lipid-linked oligosaccharides (LLO) across membranes from their cytosolic site of synthesis to their sites of utilization. Much of our current understanding of LLO transport comes from genetic, biochemical, and structural studies of the multidrug/oligosaccharidyl-lipid/polysaccharide (MOP) superfamily protein MurJ, which flips the peptidoglycan precursor lipid II. MurJ plays a pivotal role in bacterial cell wall synthesis and is an emerging antibiotic target. Here, we review the mechanism of LLO flipping by MurJ, including the structural basis for lipid II flipping and ion coupling. We then discuss inhibition of MurJ by antibacterials, including humimycins and the phage M lysis protein, as well as how studies on MurJ could provide insight into other flippases, both within and beyond the MOP superfamily.

许多重要的多糖(包括肽聚糖、脂多糖和n链聚糖)的生物合成需要脂链低聚糖(LLO)从它们的细胞质合成位点跨膜运输到它们的利用位点。我们目前对低聚糖转运的理解大部分来自多药/寡糖脂/多糖(MOP)超家族蛋白MurJ的遗传、生化和结构研究,该蛋白翻转肽聚糖前体脂质II。MurJ在细菌细胞壁合成中起着关键作用,是一种新兴的抗生素靶点。本文综述了MurJ翻转LLO的机制,包括脂质翻转和离子偶联的结构基础。然后,我们讨论了包括humimycin和噬菌体M裂解蛋白在内的抗菌素对MurJ的抑制作用,以及MurJ的研究如何为MOP超家族内外的其他翻转酶提供见解。
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引用次数: 6
Sensory TRP Channels in Three Dimensions. 三维感官 TRP 通道
IF 12.1 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2022-06-21 Epub Date: 2022-03-14 DOI: 10.1146/annurev-biochem-032620-105738
Melinda M Diver, John V Lin King, David Julius, Yifan Cheng

Transient receptor potential (TRP) ion channels are sophisticated signaling machines that detect a wide variety of environmental and physiological signals. Every cell in the body expresses one or more members of the extended TRP channel family, which consists of over 30 subtypes, each likely possessing distinct pharmacological, biophysical, and/or structural attributes. While the function of some TRP subtypes remains enigmatic, those involved in sensory signaling are perhaps best characterized and have served as models for understanding how these excitatory ion channels serve as polymodal signal integrators. With the recent resolution revolution in cryo-electron microscopy, these and other TRP channel subtypes are now yielding their secrets to detailed atomic analysis, which is beginning to reveal structural underpinnings of stimulus detection and gating, ion permeation, and allosteric mechanisms governing signal integration. These insights are providing a framework for designing and evaluating modality-specific pharmacological agents for treating sensory and other TRP channel-associated disorders.

瞬态受体电位(TRP)离子通道是一种复杂的信号机器,能检测到各种环境和生理信号。人体内的每个细胞都表达一个或多个 TRP 通道扩展家族成员,该家族由 30 多种亚型组成,每种亚型都可能具有不同的药理学、生物物理学和/或结构属性。虽然某些 TRP 亚型的功能仍然是个谜,但那些参与感觉信号传导的 TRP 亚型的特征可能是最清楚的,它们是了解这些兴奋性离子通道如何充当多模式信号整合器的模型。随着最近低温电子显微镜分辨率的革命性提高,这些和其他 TRP 通道亚型的秘密正在被详细的原子分析所揭示,从而开始揭示刺激检测和门控、离子渗透以及支配信号整合的异构机制的结构基础。这些见解为设计和评估治疗感觉和其他 TRP 通道相关疾病的特定模式药剂提供了一个框架。
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引用次数: 0
The Purinosome: A Case Study for a Mammalian Metabolon. 嘌呤酶:哺乳动物代谢物的案例研究。
IF 16.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2022-06-21 DOI: 10.1146/annurev-biochem-032620-105728
Anthony M Pedley, Vidhi Pareek, Stephen J Benkovic

Over the past fifteen years, we have unveiled a new mechanism by which cells achieve greater efficiency in de novo purine biosynthesis. This mechanism relies on the compartmentalization of de novo purine biosynthetic enzymes into a dynamic complex called the purinosome. In this review, we highlight our current understanding of the purinosome with emphasis on its biophysical properties and function and on the cellular mechanisms that regulate its assembly. We propose a model for functional purinosomes in which they consist of at least ten enzymes that localize near mitochondria and carry out de novo purine biosynthesis by metabolic channeling. We conclude by discussing challenges and opportunities associated with studying the purinosome and analogous metabolons.

在过去的15年里,我们已经揭示了一种新的机制,通过这种机制,细胞在从头合成嘌呤的过程中获得了更高的效率。这种机制依赖于新的嘌呤生物合成酶的区隔化,形成一种称为嘌呤酶体的动态复合物。在这篇综述中,我们强调了我们目前对嘌呤酶体的理解,重点是它的生物物理性质和功能以及调节其组装的细胞机制。我们提出了一种功能性嘌呤小体模型,其中它们由至少10种酶组成,这些酶位于线粒体附近,并通过代谢通道进行从头嘌呤生物合成。最后,我们讨论了与研究嘌呤酶体和类似代谢相关的挑战和机遇。
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引用次数: 15
Better, Faster, Cheaper: Recent Advances in Cryo-Electron Microscopy. 更好,更快,更便宜:冷冻电子显微镜的最新进展。
IF 16.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2022-06-21 DOI: 10.1146/annurev-biochem-032620-110705
Eugene Y D Chua, Joshua H Mendez, Micah Rapp, Serban L Ilca, Yong Zi Tan, Kashyap Maruthi, Huihui Kuang, Christina M Zimanyi, Anchi Cheng, Edward T Eng, Alex J Noble, Clinton S Potter, Bridget Carragher

Cryo-electron microscopy (cryo-EM) continues its remarkable growth as a method for visualizing biological objects, which has been driven by advances across the entire pipeline. Developments in both single-particle analysis and in situ tomography have enabled more structures to be imaged and determined to better resolutions, at faster speeds, and with more scientists having improved access. This review highlights recent advances at each stageof the cryo-EM pipeline and provides examples of how these techniques have been used to investigate real-world problems, including antibody development against the SARS-CoV-2 spike during the recent COVID-19 pandemic.

低温电子显微镜(cryo-EM)作为一种可视化生物物体的方法继续显着增长,这是由整个管道的进步所驱动的。单粒子分析和原位断层扫描技术的发展使得更多的结构能够以更高的分辨率、更快的速度进行成像和确定,更多的科学家也有了更好的途径。本综述重点介绍了低温电镜技术各个阶段的最新进展,并举例说明了这些技术如何用于研究现实世界的问题,包括在最近的COVID-19大流行期间针对SARS-CoV-2高峰的抗体开发。
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引用次数: 19
期刊
Annual review of biochemistry
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