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Understanding pyrethrin biosynthesis: toward and beyond natural pesticide overproduction. 了解除虫菊酯的生物合成:走向并超越天然杀虫剂的过度生产。
IF 3.8 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-28 DOI: 10.1042/BST20240213
Kazuhiko Matsuda

Pyrethrins are natural insecticides biosynthesised by Asteraceae plants, such as Tanacetum cinerariifolium and have a long history, dating back to ancient times. Pyrethrins are often used as low-persistence and safe insecticides to control household, horticultural, and agricultural insect pests. Despite its long history of use, pyrethrin biosynthesis remains a mystery, presenting a significant opportunity to improve yields and meet the growing demand for organic agriculture. To achieve this, both genetic modification and non-genetic methods, such as chemical activation and priming, are indispensable. Plants use pyrethrins as a defence against herbivores, but pyrethrin biosynthesis pathways are shared with plant hormones and signal molecules. Hence, the insight that pyrethrins may play broader roles than those traditionally expected is invaluable to advance the basic and applied sciences of pyrethrins.

拟除虫菊酯是由菊科植物(如丹蜱草)生物合成的天然杀虫剂,历史悠久,可追溯到古代。除虫菊素通常被用作低持久性的安全杀虫剂,用于控制家庭、园艺和农业害虫。尽管使用历史悠久,但除虫菊酯的生物合成仍然是一个谜,这为提高产量和满足日益增长的有机农业需求提供了一个重要机会。要实现这一目标,基因改造和非基因方法(如化学激活和引物)都不可或缺。植物利用除虫菊酯来抵御食草动物,但除虫菊酯的生物合成途径与植物激素和信号分子共享。因此,了解到除虫菊酯可能发挥比传统预期更广泛的作用,对于推动除虫菊酯基础科学和应用科学的发展非常有价值。
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引用次数: 0
Non-Mendelian transmission of X chromosomes: mechanisms and impact on sex ratios and population dynamics in different breeding systems. X 染色体的非孟德尔传播:机制及其对不同育种系统中性别比例和种群动态的影响。
IF 3.8 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-28 DOI: 10.1042/BST20231411
Sally Adams, Andre Pires-daSilva

The non-Mendelian transmission of sex chromosomes during gametogenesis carries significant implications, influencing sex ratios and shaping evolutionary dynamics. Here we focus on known mechanisms that drive non-Mendelian inheritance of X chromosomes during spermatogenesis and their impact on population dynamics in species with different breeding systems. In Drosophila and mice, X-linked drivers targeting Y-bearing sperm for elimination or limiting their fitness, tend to confer unfavourable effects, prompting the evolution of suppressors to mitigate their impact. This leads to a complex ongoing evolutionary arms race to maintain an equal balance of males and females. However, in certain insects and nematodes with XX/X0 sex determination, the preferential production of X-bearing sperm through atypical meiosis yields wild-type populations with highly skewed sex ratios, suggesting non-Mendelian transmission of the X may offer selective advantages in these species. Indeed, models suggest X-meiotic drivers could bolster population size and persistence under certain conditions, challenging the conventional view of their detrimental effects. Furthering our understanding of the diverse mechanisms and evolutionary consequences of non-Mendelian transmission of X chromosomes will provide insights into genetic inheritance, sex determination, and population dynamics, with implications for fundamental research and practical applications.

配子发生过程中性染色体的非孟德尔遗传具有重要意义,可影响性别比例和进化动态。在此,我们将重点研究在精子发生过程中驱动 X 染色体非孟德尔遗传的已知机制及其对不同繁殖系统物种种群动态的影响。在果蝇和小鼠中,针对含Y精子的X连锁驱动因子往往会产生不利影响,从而导致抑制因子的进化,以减轻其影响。这导致了一场复杂的持续进化军备竞赛,以维持雌雄平衡。然而,在某些性别决定为 XX/X0 的昆虫和线虫中,通过非典型减数分裂优先产生含 X 的精子,从而产生了性别比例高度倾斜的野生型种群。事实上,模型表明,在某些条件下,X-减数分裂的驱动力可以增强种群的规模和持续性,这对传统的有害影响观点提出了挑战。进一步了解 X 染色体非孟德尔传递的各种机制和进化后果,将有助于我们深入了解遗传、性别决定和种群动态,并对基础研究和实际应用产生影响。
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引用次数: 0
Plant supercomplex I + III2 structure and function: implications for the growing field. 植物超级复合体 I + III2 的结构和功能:对不断发展的领域的影响。
IF 3.8 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-28 DOI: 10.1042/BST20230947
Maria Maldonado

Mitochondrial respiration is major source of chemical energy for all free-living eukaryotes. Nevertheless, the mechanisms of the respiratory complexes and supercomplexes remain poorly understood. Here, I review recent structural and functional investigations of plant supercomplex I + III2 from Arabidopsis thaliana and Vigna radiata. I discuss commonalities, open questions and implications for complex I, complex III2 and supercomplexes in plants and non-plants. Studies across further clades will enhance our understanding of respiration and the potential universal mechanisms of its complexes and supercomplexes.

线粒体呼吸是所有自由生活真核生物的主要化学能量来源。然而,人们对呼吸复合体和超级复合体的机制仍然知之甚少。在此,我回顾了最近对拟南芥和黑叶木槿植物超级复合物 I + III2 的结构和功能研究。我将讨论植物和非植物中复合体 I、复合体 III2 和超级复合体的共性、未决问题和影响。对更多支系的研究将增进我们对呼吸作用及其复合体和超级复合体潜在普遍机制的了解。
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引用次数: 0
Progress in multifactorial single-cell chromatin profiling methods. 多因素单细胞染色质谱分析方法的进展。
IF 3.8 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-28 DOI: 10.1042/BST20231471
Tim Stuart

Chromatin states play a key role in shaping overall cellular states and fates. Building a complete picture of the functional state of chromatin in cells requires the co-detection of several distinct biochemical aspects. These span DNA methylation, chromatin accessibility, chromosomal conformation, histone posttranslational modifications, and more. While this certainly presents a challenging task, over the past few years many new and creative methods have been developed that now enable co-assay of these different aspects of chromatin at single cell resolution. This field is entering an exciting phase, where a confluence of technological improvements, decreased sequencing costs, and computational innovation are presenting new opportunities to dissect the diversity of chromatin states present in tissues, and how these states may influence gene regulation. In this review, I discuss the spectrum of current experimental approaches for multifactorial chromatin profiling, highlight some of the experimental and analytical challenges, as well as some areas for further innovation.

染色质状态在塑造细胞整体状态和命运方面发挥着关键作用。要全面了解细胞中染色质的功能状态,需要同时检测多个不同的生化方面。这些方面包括 DNA 甲基化、染色质可及性、染色体构象、组蛋白翻译后修饰等。虽然这无疑是一项具有挑战性的任务,但在过去几年中,许多新的创造性方法已经开发出来,现在可以在单细胞分辨率下对染色质的这些不同方面进行联合检测。这一领域正进入一个令人兴奋的阶段,技术的改进、测序成本的降低和计算的创新为剖析组织中染色质状态的多样性以及这些状态如何影响基因调控提供了新的机遇。在这篇综述中,我将讨论当前多因素染色质图谱分析的各种实验方法,强调一些实验和分析方面的挑战,以及一些有待进一步创新的领域。
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引用次数: 0
Understanding P-Rex regulation: structural breakthroughs and emerging perspectives. 了解 P-Rex 调节:结构性突破和新观点。
IF 3.8 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-28 DOI: 10.1042/BST20231546
Gareth D Jones, Andrew M Ellisdon

Rho GTPases are a family of highly conserved G proteins that regulate numerous cellular processes, including cytoskeleton organisation, migration, and proliferation. The 20 canonical Rho GTPases are regulated by ∼85 guanine nucleotide exchange factors (GEFs), with the largest family being the 71 Diffuse B-cell Lymphoma (Dbl) GEFs. Dbl GEFs promote GTPase activity through the highly conserved Dbl homology domain. The specificity of GEF activity, and consequently GTPase activity, lies in the regulation and structures of the GEFs themselves. Dbl GEFs contain various accessory domains that regulate GEF activity by controlling subcellular localisation, protein interactions, and often autoinhibition. This review focuses on the two phosphatidylinositol (3,4,5)-trisphosphate (PI(3,4,5)P3)-dependent Rac exchangers (P-Rex), particularly the structural basis of P-Rex1 autoinhibition and synergistic activation. First, we discuss structures that highlight the conservation of P-Rex catalytic and phosphoinositide binding activities. We then explore recent breakthroughs in uncovering the structural basis for P-Rex1 autoinhibition and detail the proposed minimal two-step model of how PI(3,4,5)P3 and Gβγ synergistically activate P-Rex1 at the membrane. Additionally, we discuss the further layers of P-Rex regulation provided by phosphorylation and P-Rex2-PTEN coinhibitory complex formation, although these mechanisms remain incompletely understood. Finally, we leverage the available data to infer how cancer-associated mutations in P-Rex2 destabilise autoinhibition and evade PTEN coinhibitory complex formation, leading to increased P-Rex2 GEF activity and driving cancer progression and metastasis.

Rho GTPases 是一个高度保守的 G 蛋白家族,可调控细胞骨架组织、迁移和增殖等多种细胞过程。20 个典型的 Rho GTP 酶受 ∼85 个鸟嘌呤核苷酸交换因子(GEFs)的调控,其中最大的家族是 71 个弥漫性 B 细胞淋巴瘤(Dbl)GEFs。Dbl GEFs 通过高度保守的 Dbl 同源结构域促进 GTPase 活性。GEF 活性以及 GTPase 活性的特异性在于 GEF 本身的调节和结构。Dbl GEF 含有各种附属结构域,它们通过控制亚细胞定位、蛋白质相互作用以及通常的自身抑制作用来调节 GEF 的活性。本综述将重点讨论两种依赖于磷脂酰肌醇(3,4,5)三磷酸酯(PI(3,4,5)P3)的 Rac 交换子(P-Rex),尤其是 P-Rex1 自身抑制和协同激活的结构基础。首先,我们讨论了突显 P-Rex 催化和磷酸肌醇结合活性保守性的结构。然后,我们探讨了最近在揭示 P-Rex1 自身抑制的结构基础方面取得的突破,并详细介绍了所提出的 PI(3,4,5)P3 和 Gβγ 如何在膜上协同激活 P-Rex1 的最小两步模型。此外,我们还讨论了磷酸化和 P-Rex2-PTEN 共抑制复合物形成对 P-Rex 调控的进一步影响,尽管对这些机制的了解仍不全面。最后,我们利用现有数据推断与癌症相关的 P-Rex2 基因突变是如何破坏自抑制稳定性并逃避 PTEN 共抑制复合物的形成,从而导致 P-Rex2 GEF 活性增加并推动癌症进展和转移的。
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引用次数: 0
Enzymes of sphingolipid metabolism as transducers of metabolic inputs. 鞘脂代谢酶是新陈代谢输入的转换器。
IF 3.8 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-28 DOI: 10.1042/BST20231442
Fabiola N Velazquez, Chiara Luberto, Daniel Canals, Yusuf A Hannun

Sphingolipids (SLs) constitute a discrete subdomain of metabolism, and they display both structural and signaling functions. Accumulating evidence also points to intimate connections between intermediary metabolism and SL metabolism. Given that many SLs exhibit bioactive properties (i.e. transduce signals), these raise the possibility that an important function of SLs is to relay information on metabolic changes into specific cell responses. This could occur at various levels. Some metabolites are incorporated into SLs, whereas others may initiate regulatory or signaling events that, in turn, modulate SL metabolism. In this review, we elaborate on the former as it represents a poorly appreciated aspect of SL metabolism, and we develop the hypothesis that the SL network is highly sensitive to several specific metabolic changes, focusing on amino acids (serine and alanine), various fatty acids, choline (and ethanolamine), and glucose.

鞘磷脂(SL)是新陈代谢的一个独立子域,具有结构和信号功能。不断积累的证据还表明,中间代谢与鞘磷脂代谢之间存在密切联系。鉴于许多可溶性脂质具有生物活性(即传递信号),这就提出了一种可能性,即可溶性脂质的一个重要功能是将新陈代谢变化的信息传递给特定的细胞反应。这可能发生在不同层面。一些代谢物被纳入 SL,而另一些代谢物则可能启动调节或信号事件,进而调节 SL 的代谢。在这篇综述中,我们阐述了前者,因为它代表了 SL 代谢中一个鲜为人知的方面,我们提出了 SL 网络对几种特定代谢变化高度敏感的假设,重点是氨基酸(丝氨酸和丙氨酸)、各种脂肪酸、胆碱(和乙醇胺)和葡萄糖。
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引用次数: 0
Computational design of de novo bioenergetic membrane proteins. 全新生物能膜蛋白的计算设计。
IF 3.8 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-28 DOI: 10.1042/BST20231347
Benjamin J Hardy, Paul Curnow

The major energy-producing reactions of biochemistry occur at biological membranes. Computational protein design now provides the opportunity to elucidate the underlying principles of these processes and to construct bioenergetic pathways on our own terms. Here, we review recent achievements in this endeavour of 'synthetic bioenergetics', with a particular focus on new enabling tools that facilitate the computational design of biocompatible de novo integral membrane proteins. We use recent examples to showcase some of the key computational approaches in current use and highlight that the overall philosophy of 'surface-swapping' - the replacement of solvent-facing residues with amino acids bearing lipid-soluble hydrophobic sidechains - is a promising avenue in membrane protein design. We conclude by highlighting outstanding design challenges and the emerging role of AI in sequence design and structure ideation.

生物化学的主要能量生成反应都发生在生物膜上。现在,计算蛋白质设计为阐明这些过程的基本原理和根据我们自己的条件构建生物能途径提供了机会。在此,我们回顾了 "合成生物能量学 "这一研究领域的最新成果,并重点介绍了有助于计算设计生物相容性全新整体膜蛋白的新工具。我们用最近的例子展示了目前使用的一些关键计算方法,并强调了 "表面交换 "的整体理念--用带有脂溶性疏水侧链的氨基酸取代面向溶剂的残基--是膜蛋白设计中的一条大有可为的途径。最后,我们强调了尚未解决的设计难题以及人工智能在序列设计和结构构思中的新兴作用。
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引用次数: 0
Mechanisms of lysosomal tubulation and sorting driven by LRRK2. LRRK2 驱动溶酶体管化和分选的机制。
IF 3.8 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-28 DOI: 10.1042/BST20240087
Luis Bonet-Ponce, Jillian H Kluss, Mark R Cookson

Lysosomes are dynamic cellular structures that adaptively remodel their membrane in response to stimuli, including membrane damage. Lysosomal dysfunction plays a central role in the pathobiology of Parkinson's disease (PD). Gain-of-function mutations in Leucine-rich repeat kinase 2 (LRRK2) cause familial PD and genetic variations in its locus increase the risk of developing the sporadic form of the disease. We previously uncovered a process we term LYTL (LYsosomal Tubulation/sorting driven by LRRK2), wherein membrane-damaged lysosomes generate tubules sorted into mobile vesicles. Subsequently, these vesicles interact with healthy lysosomes. LYTL is orchestrated by LRRK2 kinase activity, via the recruitment and phosphorylation of a subset of RAB GTPases. Here, we summarize the current understanding of LYTL and its regulation, as well as the unknown aspects of this process.

溶酶体是一种动态的细胞结构,能对包括膜损伤在内的各种刺激做出反应,适应性地重塑其膜。溶酶体功能障碍在帕金森病(PD)的病理生物学中起着核心作用。富亮氨酸重复激酶 2(LRRK2)的功能增益突变会导致家族性帕金森病,而其基因位点的遗传变异会增加患散发性帕金森病的风险。我们之前发现了一个被称为LYTL(LRRK2驱动的溶酶体管化/分选)的过程,在这一过程中,膜受损的溶酶体生成管状小泡,并分选成移动小泡。随后,这些小泡与健康的溶酶体相互作用。LYTL 是由 LRRK2 激酶活性通过招募和磷酸化 RAB GTP 酶子集来协调的。在此,我们总结了目前对 LYTL 及其调控的理解,以及这一过程的未知方面。
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引用次数: 0
Transcriptional bursting: from fundamentals to novel insights. 转录突变:从基本原理到新见解。
IF 3.8 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-28 DOI: 10.1042/BST20231286
Daniel Hebenstreit, Pradip Karmakar

Transcription occurs as irregular bursts in a very wide range of systems, including numerous different species and many genes within these. In this review, we examine the underlying theories, discuss how these relate to experimental measurements, and explore some of the discrepancies that have emerged among various studies. Finally, we consider more recent works that integrate novel concepts, such as the involvement of biomolecular condensates in enhancer-promoter interactions and their effects on the dynamics of transcriptional bursting.

转录以不规则的爆发形式出现在非常广泛的系统中,包括许多不同的物种和这些物种中的许多基因。在这篇综述中,我们研究了相关理论,讨论了这些理论与实验测量之间的关系,并探讨了不同研究之间出现的一些差异。最后,我们还将探讨整合了新概念的最新研究成果,如生物分子凝聚体参与增强子-启动子相互作用及其对转录猝发动态的影响。
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引用次数: 0
Making cups and rings: the 'stalled-wave' model for macropinocytosis. 制造杯子和圆环:大蛋白细胞的 "停滞波 "模型
IF 3.8 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-28 DOI: 10.1042/BST20231426
Robert R Kay, Judith E Lutton, Jason S King, Till Bretschneider

Macropinocytosis is a broadly conserved endocytic process discovered nearly 100 years ago, yet still poorly understood. It is prominent in cancer cell feeding, immune surveillance, uptake of RNA vaccines and as an invasion route for pathogens. Macropinocytic cells extend large cups or flaps from their plasma membrane to engulf droplets of medium and trap them in micron-sized vesicles. Here they are digested and the products absorbed. A major problem - discussed here - is to understand how cups are shaped and closed. Recently, lattice light-sheet microscopy has given a detailed description of this process in Dictyostelium amoebae, leading to the 'stalled-wave' model for cup formation and closure. This is based on membrane domains of PIP3 and active Ras and Rac that occupy the inner face of macropinocytic cups and are readily visible with suitable reporters. These domains attract activators of dendritic actin polymerization to their periphery, creating a ring of protrusive F-actin around themselves, thus shaping the walls of the cup. As domains grow, they drive a wave of actin polymerization across the plasma membrane that expands the cup. When domains stall, continued actin polymerization under the membrane, combined with increasing membrane tension in the cup, drives closure at lip or base. Modelling supports the feasibility of this scheme. No specialist coat proteins or contractile activities are required to shape and close cups: rings of actin polymerization formed around PIP3 domains that expand and stall seem sufficient. This scheme may be widely applicable and begs many biochemical questions.

大核细胞吞噬是近 100 年前发现的一种广泛保守的内吞过程,但人们对它的了解仍然很少。它在癌细胞摄食、免疫监视、RNA 疫苗的吸收以及病原体的入侵途径等方面发挥着重要作用。巨核细胞从其质膜上伸出大杯或大瓣来吞噬介质液滴,并将其截留在微米大小的囊泡中。它们在这里被消化,产物被吸收。这里讨论的一个主要问题是了解杯是如何形成和闭合的。最近,格子光片显微镜详细描述了竹节虫变形虫的这一过程,从而提出了杯状体形成和闭合的 "停滞波 "模型。该模型的基础是 PIP3 和活性 Ras 及 Rac 的膜域,这些膜域占据大突胶质细胞杯的内面,用合适的报告器很容易看到。这些膜域将树突肌动蛋白聚合激活剂吸引到其外围,在自身周围形成一个突出的 F-肌动蛋白环,从而形成杯壁。随着结构域的生长,它们会驱动肌动蛋白聚合波穿过质膜,从而扩大杯壁。当结构域停滞时,膜下的肌动蛋白继续聚合,再加上杯中膜张力的增加,促使杯唇或杯底闭合。模型支持这一方案的可行性。杯状结构的形成和闭合不需要专门的衣壳蛋白或收缩活动:围绕 PIP3 结构域形成的肌动蛋白聚合环膨胀和停滞似乎就足够了。这一方案可能具有广泛的适用性,并提出了许多生化问题。
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引用次数: 0
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