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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, Genetics and 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 Design and Application of DNA-Editing Enzymes as Base Editors. 作为碱基编辑器的 DNA 编辑酶的设计与应用。
IF 12.1 1区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-06-20 Epub Date: 2023-04-05 DOI: 10.1146/annurev-biochem-052521-013938
Kartik L Rallapalli, Alexis C Komor

DNA-editing enzymes perform chemical reactions on DNA nucleobases. These reactions can change the genetic identity of the modified base or modulate gene expression. Interest in DNA-editing enzymes has burgeoned in recent years due to the advent of clustered regularly interspaced short palindromic repeat-associated (CRISPR-Cas) systems, which can be used to direct their DNA-editing activity to specific genomic loci of interest. In this review, we showcase DNA-editing enzymes that have been repurposed or redesigned and developed into programmable base editors. These include deaminases, glycosylases, methyltransferases, and demethylases. We highlight the astounding degree to which these enzymes have been redesigned, evolved, and refined and present these collective engineering efforts as a paragon for future efforts to repurpose and engineer other families of enzymes. Collectively, base editors derived from these DNA-editing enzymes facilitate programmable point mutation introduction and gene expression modulation by targeted chemical modification of nucleobases.

DNA 编辑酶对 DNA 核碱基进行化学反应。这些反应可以改变被修饰碱基的遗传特性或调节基因表达。近年来,由于聚类规则间距短回文重复相关(CRISPR-Cas)系统的出现,人们对DNA编辑酶的兴趣急剧增加。在这篇综述中,我们展示了被重新利用或重新设计并开发成可编程碱基编辑器的DNA编辑酶。这些酶包括脱氨酶、糖基化酶、甲基转移酶和去甲基化酶。我们强调了这些酶被重新设计、进化和完善的惊人程度,并介绍了这些集体工程努力,作为未来重新利用和工程化其他酶家族的典范。总的来说,从这些 DNA 编辑酶中衍生出来的碱基编辑器通过对核酸进行有针对性的化学修饰,促进了可编程点突变的引入和基因表达的调控。
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引用次数: 0
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, Genetics and 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
mRNA Regulation by RNA Modifications. 通过 RNA 修饰调节 mRNA。
IF 12.1 1区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-06-20 Epub Date: 2023-04-05 DOI: 10.1146/annurev-biochem-052521-035949
Wendy V Gilbert, Sigrid Nachtergaele

Chemical modifications on mRNA represent a critical layer of gene expression regulation. Research in this area has continued to accelerate over the last decade, as more modifications are being characterized with increasing depth and breadth. mRNA modifications have been demonstrated to influence nearly every step from the early phases of transcript synthesis in the nucleus through to their decay in the cytoplasm, but in many cases, the molecular mechanisms involved in these processes remain mysterious. Here, we highlight recent work that has elucidated the roles of mRNA modifications throughout the mRNA life cycle, describe gaps in our understanding and remaining open questions, and offer some forward-looking perspective on future directions in the field.

mRNA 上的化学修饰是基因表达调控的一个重要层面。在过去十年中,这一领域的研究持续加速,越来越多的修饰被表征出来,其深度和广度也在不断增加。mRNA修饰已被证明影响着从转录本在细胞核中合成的早期阶段到在细胞质中衰变的几乎每一个步骤,但在许多情况下,这些过程所涉及的分子机制仍然是神秘的。在这里,我们将重点介绍最近阐明了 mRNA 修饰在整个 mRNA 生命周期中的作用的研究工作,描述我们在理解上的差距和仍未解决的问题,并对该领域的未来发展方向提出一些前瞻性的观点。
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引用次数: 0
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, Genetics and 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, Genetics and 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
The Life of SARS-CoV-2 Inside Cells: Replication-Transcription Complex Assembly and Function. SARS-CoV-2在细胞内的生命:复制-转录复合体的组装和功能
IF 16.6 1区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2022-06-21 DOI: 10.1146/annurev-biochem-052521-115653
Zhiyong Lou, Zihe Rao

The persistence of the coronavirus disease 2019 (COVID-19) pandemic has resulted in increasingly disruptive impacts, and it has become the most devastating challenge to global health in a century. The rapid emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants challenges the currently available therapeutics for clinical application. Nonstructural proteins (also known as replicase proteins) with versatile biological functions play central roles in viral replication and transcription inside the host cells, and they are the most conserved target proteins among the SARS-CoV-2 variants. Specifically, they constitute the replication-transcription complexes (RTCs) dominating the synthesis of viral RNA. Knowledge of themolecular mechanisms of nonstructural proteins and their assembly into RTCs will benefit the development of antivirals targeting them against existing or potentially emerging variants. In this review, we summarize current knowledge of the structures and functions of coronavirus nonstructural proteins as well as the assembly and functions of RTCs in the life cycle of the virus.

2019年冠状病毒病(COVID-19)大流行的持续造成了越来越大的破坏性影响,已成为一个世纪以来全球卫生面临的最具破坏性的挑战。严重急性呼吸综合征冠状病毒2 (SARS-CoV-2)变体的迅速出现对目前临床应用的现有治疗方法提出了挑战。具有多种生物学功能的非结构蛋白(也称为复制酶蛋白)在宿主细胞内的病毒复制和转录中起着核心作用,是SARS-CoV-2变体中最保守的靶蛋白。具体来说,它们构成了主导病毒RNA合成的复制转录复合物(rtc)。了解非结构蛋白的分子机制及其在rtc中的组装将有助于开发针对现有或潜在变异的抗病毒药物。本文综述了冠状病毒非结构蛋白的结构和功能,以及rtc在病毒生命周期中的组装和功能。
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引用次数: 6
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, Genetics and 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
期刊
Annual review of biochemistry
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