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Nature论文导读 1026

时间: 2017年11月06日 | 作者: admin | 来源: 未知
Nature 20171026 1 【生物】 Disorder in convergent floral nanostructures enhances signalling to bees Edwige Moyroud et.al 趋同进化产生的无序花朵纳米结构可增强对蜜蜂的信号传递 https://www.nature.com/nature/journa

Nature 20171026

1【生物】Disorder in convergent floral nanostructures enhances signalling to bees


Edwige Moyroud et.al







Diverse forms of nanoscale architecture generate structural colour and perform signalling functions within and between species. Structural colour is the result of the interference of light from approximately regular periodic structures; some structural disorder is, however, inevitable in biological organisms. Is this disorder functional and subject to evolutionary selection, or is it simply an unavoidable outcome of biological developmental processes? Here we show that disordered nanostructures enable flowers to produce visual signals that are salient to bees. These disordered nanostructures (identified in most major lineages of angiosperms) have distinct anatomies but convergent optical properties; they all produce angle-dependent scattered light, predominantly at short wavelengths (ultraviolet and blue). We manufactured artificial flowers with nanoscale structures that possessed tailored levels of disorder in order to investigate how foraging bumblebees respond to this optical effect. We conclude that floral nanostructures have evolved, on multiple independent occasions, an effective degree of relative spatial disorder that generates a photonic signature that is highly salient to insect pollinators.


(导读 郭怿暄)光线在周期性的纳米结构上发生干涉可产生结构性色彩,并在物种内及物种间发挥信号功能。 虽然生物中无序的结构不可避免,本研究发现绝大多数被子植物花朵的无规则纳米结构尽管解剖结构各异,但具有相同光学特性,可产生以短波为主、角度依赖的散射光线。这些通过多次独立进化而来、空间上的相对无序达到一定的有效水平,为传粉昆虫提供突出的光电子视觉信号。


2 【生物】Inflammatory memory sensitizes skin epithelial stem cells to tissue damage


Shruti Naik et.al







The skin barrier is the body’s first line of defence against environmental assaults, and is maintained by epithelial stem cells (EpSCs). Despite the vulnerability of EpSCs to inflammatory pressures, neither the primary response to inflammation nor its enduring consequences are well understood. Here we report a prolonged memory to acute inflammation that enables mouse EpSCs to hasten barrier restoration after subsequent tissue damage. This functional adaptation does not require skin-resident macrophages or T cells. Instead, EpSCs maintain chromosomal accessibility at key stress response genes that are activated by the primary stimulus. Upon a secondary challenge, genes governed by these domains are transcribed rapidly. Fuelling this memory is Aim2, which encodes an activator of the inflammasome. The absence of AIM2 or its downstream effectors, caspase-1 and interleukin-1β, erases the ability of EpSCs to recollect inflammation. Although EpSCs benefit from inflammatory tuning by heightening their responsiveness to subsequent stressors, this enhanced sensitivity probably increases their susceptibility to autoimmune and hyperproliferative disorders, including cancer.


(导读 郭怿暄)皮肤是身体对于各种环境伤害的第一道防线,上皮干细胞(EpSCs)负责维持这道屏障的完整。本研究发现对于急性炎症反应的延长记忆使得小鼠EpSCs可以在后续的组织损伤中加快皮肤屏障功能的恢复。原始刺激激活的主要应激反应基因在EpSCs都保持了染色体可进入性,并在二次刺激后迅速转录。其中编码炎症小体中激活因子的Aim2及其下游因子对这一记忆反应发挥重要作用。



3 【生物】Molecular basis of USP7 inhibition by selective small-molecule inhibitors


Andrew P. Turnbull, et.al






Ubiquitination controls the stability of most cellular proteins, and its deregulation contributes to human diseases including cancer. Deubiquitinases remove ubiquitin from proteins, and their inhibition can induce the degradation of selected proteins, potentially including otherwise ‘undruggable’ targets. For example, the inhibition of ubiquitin-specific protease 7 (USP7) results in the degradation of the oncogenic E3 ligase MDM2, and leads to re-activation of the tumour suppressor p53 in various cancers. Here we report that two compounds, FT671 and FT827, inhibit USP7 with high affinity and specificity in vitro and within human cells. Co-crystal structures reveal that both compounds target a dynamic pocket near the catalytic centre of the auto-inhibited apo form of USP7, which differs from other USP deubiquitinases. Consistent with USP7 target engagement in cells, FT671 destabilizes USP7 substrates including MDM2, increases levels of p53, and results in the transcription of p53 target genes, induction of the tumour suppressor p21, and inhibition of tumour growth in mice.


(导读 郭怿暄)去泛素化酶可去除蛋白质上的泛素化修饰,抑制去泛素化酶可提高其底物蛋白的泛素化水平,促进其降解。本研究发现化合物FT671和FT827可在体外和人类细胞中高亲和性、高选择性地抑制去泛素化酶USP7,使得其底物致癌蛋白MDM2的稳定性下降,进而重新激活细胞中肿瘤抑制因子p53及其靶向基因的转录、诱导p21,抑制小鼠肿瘤的生长。



4 【材料】Structural phase transition in monolayer MoTe2 driven by electrostatic doping

Ying Wang, et.al



(导读 阿金)过渡金属二硫属化合物的单分子层呈现大量结构、物理性质不同的晶相,它们之间的结构相变一般通过温控或化学方法来诱导。本研究在实验上实现了静电掺杂驱动的单分子层二碲化钼(MoTe2)的结构相变。该相变的拉曼光谱中显示出一个滞后环,并且可以通过增加或减少栅极电压实现相变反转。


Monolayers of transition-metal dichalcogenides (TMDs) exhibit numerous crystal phases with distinct structures, symmetries and physical properties. Exploring the physics of transitions between these different structural phases in two dimensions may provide a means of switching material properties, with implications for potential applications. Structural phase transitions in TMDs have so far been induced by thermal or chemical means; purely electrostatic control over crystal phases through electrostatic doping was recently proposed as a theoretical possibility, but has not yet been realized. Here we report the experimental demonstration of an electrostatic-doping-driven phase transition between the hexagonal and monoclinic phases of monolayer molybdenum ditelluride (MoTe2). We find that the phase transition shows a hysteretic loop in Raman spectra, and can be reversed by increasing or decreasing the gate voltage. We also combine second-harmonic generation spectroscopy with polarization-resolved Raman spectroscopy to show that the induced monoclinic phase preserves the crystal orientation of the original hexagonal phase. Moreover, this structural phase transition occurs simultaneously across the whole sample. This electrostatic-doping control of structural phase transition opens up new possibilities for developing phase-change devices based on atomically thin membranes.


5【化学】Probing the limits of metal plasticity with molecular dynamics simulations

Luis A. Zepeda-Ruiz, et.al



(导读 阿金)金属的强度和可塑性由位错来定义,但用位错动力学模型来模拟原子动力学往往计算成本高且精度不够。本研究展示了对金属可塑性的全动态原子水平模拟,研究体心立方金属响应超高应变率而发生的变形。结果发现金属在到达极限条件时,仅靠位错无法缓解机械载荷,变形孪晶将成为主要的动态响应模式。


Ordinarily, the strength and plasticity properties of a metal are defined by dislocations—line defects in the crystal lattice whose motion results in material slippage along lattice planes. Dislocation dynamics models are usually used as mesoscale proxies for true atomistic dynamics, which are computationally expensive to perform routinely. However, atomistic simulations accurately capture every possible mechanism of material response, resolving every “jiggle and wiggle” of atomic motion, whereas dislocation dynamics models do not. Here we present fully dynamic atomistic simulations of bulk single-crystal plasticity in the body-centred-cubic metal tantalum. Our goal is to quantify the conditions under which the limits of dislocation-mediated plasticity are reached and to understand what happens to the metal beyond any such limit. In our simulations, the metal is compressed at ultrahigh strain rates along its [001] crystal axis under conditions of constant pressure, temperature and strain rate. To address the complexity of crystal plasticity processes on the length scales (85–340nm) and timescales (1 ns–1μs) that we examine, we use recently developed methods of in situ computational microscopy4, 5 to recast the enormous amount of transient trajectory data generated in our simulations into a form that can be analysed by a human. Our simulations predict that, on reaching certain limiting conditions of strain, dislocations alone can no longer relieve mechanical loads; instead, another mechanism, known as deformation twinning (the sudden re-orientation of the crystal lattice6), takes over as the dominant mode of dynamic response. Below this limit, the metal assumes a strain-path-independent steady state of plastic flow in which the flow stress and the dislocation density remain constant as long as the conditions of straining thereafter remain unchanged. In this distinct state, tantalum flows like a viscous fluid while retaining its crystal lattice and remaining a strong and stiff metal.


6 【材料】In situ X-ray diffraction measurement of shock-wave-driven twinning and lattice dynamics

C. E. Wehrenberg, et.al



(导读 阿金)压力冲击波会造成固体材料变形,在晶格层面这种塑性变形的机制是和滑移变形。本研究在体心立方金属进行了飞秒分辨率的X射线衍射实验,捕捉晶格层面上的导致冲击波驱动变形的微结构过程信息。结果揭示,在几十皮秒的时间尺度上出现了和相关晶格旋转。此外,在高压情况下,可塑性从晶主导转变到位错滑移主导。该技术可用于研究冲击波和其他高应变率现象。


Pressure-driven shock waves in solid materials can cause extreme damage and deformation. Understanding this deformation and the associated defects that are created in the material is crucial in the study of a wide range of phenomena, including planetary formation and asteroid impact sites, the formation of interstellar dust clouds, ballistic penetrators, spacecraft shielding and ductility in high-performance ceramics. At the lattice level, the basic mechanisms of plastic deformation are twinning (whereby crystallites with a mirror-image lattice form) and slip (whereby lattice dislocations are generated and move), but determining which of these mechanisms is active during deformation is challenging. Experiments that characterized lattice defects have typically examined the microstructure of samples after deformation, and so are complicated by post-shock annealing and reverberations. In addition, measurements have been limited to relatively modest pressures (less than 100 gigapascals). In situ X-ray diffraction experiments can provide insights into the dynamic behaviour of materials, but have only recently been applied to plasticity during shock compression and have yet to provide detailed insight into competing deformation mechanisms. Here we present X-ray diffraction experiments with femtosecond resolution that capture in situ, lattice-level information on the microstructural processes that drive shock-wave-driven deformation. To demonstrate this method we shock-compress the body-centred-cubic material tantalum—an important material for high-energy-density physics owing to its high shock impedance and high X-ray opacity. Tantalum is also a material for which previous shock compression simulations and experiments have provided conflicting information about the dominant deformation mechanism. Our experiments reveal twinning and related lattice rotation occurring on the timescale of tens of picoseconds. In addition, despite the common association between twinning and strong shocks, we find a transition from twinning to dislocation-slip-dominated plasticity at high pressure (more than 150 gigapascals), a regime that recovery experiments cannot accurately access. The techniques demonstrated here will be useful for studying shock waves and other high-strain-rate phenomena, as well as a broad range of processes induced by plasticity.



7【生物】Inertial picobalance reveals fast mass fluctuations in mammalian cells

David Martínez-Martín, et.al



(导读 阿金)本研究报告一种基于光学激发的微共振细胞平衡器picobalance,它可以以毫秒时间分辨率和皮克质量灵敏度,在生理状态下测量单个或多个粘连细胞在几天内的细胞质量动态变化。利用该技术,本研究对哺乳动物活细胞在整个细胞周期内的质量波动情况进行测量,并探讨了波动的机制。本技术可与荧光成像等传统技术共用,可以为细胞质量调节相关研究提供支持。


The regulation of size, volume and mass in living cells is physiologically important, and dysregulation of these parameters gives rise to many diseases. Cell mass is largely determined by the amount of water, proteins, lipids, carbohydrates and nucleic acids present in a cell, and is tightly linked to metabolism, proliferation and gene expression. Technologies have emerged in recent years that make it possible to track the masses of single suspended cells and adherent cells. However, it has not been possible to track individual adherent cells in physiological conditions at the mass and time resolutions required to observe fast cellular dynamics. Here we introduce a cell balance (a ‘picobalance’), based on an optically excited microresonator, that measures the total mass of single or multiple adherent cells in culture conditions over days with millisecond time resolution and picogram mass sensitivity. Using our technique, we observe that the mass of living mammalian cells fluctuates intrinsically by around one to four per cent over timescales of seconds throughout the cell cycle. Perturbation experiments link these mass fluctuations to the basic cellular processes of ATP synthesis and water transport. Furthermore, we show that growth and cell cycle progression are arrested in cells infected with vaccinia virus, but mass fluctuations continue until cell death. Our measurements suggest that all living cells show fast and subtle mass fluctuations throughout the cell cycle. As our cell balance is easy to handle and compatible with fluorescence microscopy, we anticipate that our approach will contribute to the understanding of cell mass regulation in various cell states and across timescales, which is important in areas including physiology, cancer research, stem-cell differentiation and drug discovery.


8【地球科学 】Evidence of marine ice-cliff instability in Pine Island Bay from iceberg-keel plough marks


Matthew G. Wise, et.al






Marine ice-cliff instability (MICI) processes could accelerate future retreat of the Antarctic Ice Sheet if ice shelves that buttress grounding lines more than 800 metres below sea level are lost. The present-day grounding zones of the Pine Island and Thwaites glaciers in West Antarctica need to retreat only short distances before they reach extensive retrograde slopes. When grounding zones of glaciers retreat onto such slopes, theoretical considerations and modelling results indicate that the retreat becomes unstable (marine ice-sheet instability) and thus accelerates. It is thought that MICI is triggered when this retreat produces ice cliffs above the water line with heights approaching about 90 metres. However, observational evidence confirming the action of MICI has not previously been reported. Here we present observational evidence that rapid deglacial ice-sheet retreat into Pine Island Bay proceeded in a similar manner to that simulated in a recent modelling study, driven by MICI. Iceberg-keel plough marks on the sea-floor provide geological evidence of past and present iceberg morphology, keel depth and drift direction. From the planform shape and cross-sectional morphologies of iceberg-keel plough marks, we find that iceberg calving during the most recent deglaciation was not characterized by small numbers of large, tabular icebergs as is observed today which would produce wide, flat-based plough marks10 or toothcomb-like multi-keeled plough marks. Instead, it was characterized by large numbers of smaller icebergs with V-shaped keels. Geological evidence of the form and water-depth distribution of the plough marks indicates calving-margin thicknesses equivalent to the threshold that is predicted to trigger ice-cliff structural collapse as a result of MICI. We infer rapid and sustained ice-sheet retreat driven by MICI, commencing around 12,300 years ago and terminating before about 11,200 years ago, which produced large numbers of icebergs smaller than the typical tabular icebergs produced today. Our findings demonstrate the effective operation of MICI in the past, and highlight its potential contribution to accelerated future retreat of the Antarctic Ice Sheet.


(导读 刘晓娟)海洋冰崖不稳定(MICI)过程可能加速未来南极冰盖的退缩。本研究表明,松岛弯冰川快速消融过程与MICI驱动的模拟方式类似。海床上的冰山龙骨犁痕提供了冰山形态,龙骨深度和漂移方向的地质证据。我们推断由MICI驱动的冰盖消退开始于12300年前,结束于11200年前,导致大量的冰山比现代典型的平顶冰山小。研究结果表明MICI的有效性,并强调它对未来加速南极冰盖消退的潜在贡献。



9【生态】Indirect effects drive coevolution in mutualistic networks


Paulo R. Guimarães Jr, et.al






Ecological interactions have been acknowledged to play a key role in shaping biodiversity. Yet a major challenge for evolutionary biology is to understand the role of ecological interactions in shaping trait evolution when progressing from pairs of interacting species to multispecies interaction networks. Here we introduce an approach that integrates coevolutionary dynamics and network structure. Our results show that non-interacting species can be as important as directly interacting species in shaping coevolution within mutualistic assemblages. The contribution of indirect effects differs among types of mutualism. Indirect effects are more likely to predominate in nested, species-rich networks formed by multiple-partner mutualisms, such as pollination or seed dispersal by animals, than in small and modular networks formed by intimate mutualisms, such as those between host plants and their protective ants. Coevolutionary pathways of indirect effects favour ongoing trait evolution by promoting slow but continuous reorganization of the adaptive landscape of mutualistic partners under changing environments. Our results show that coevolution can be a major process shaping species traits throughout ecological networks. These findings expand our understanding of how evolution driven by interactions occurs through the interplay of selection pressures moving along multiple direct and indirect pathways.



(导读 刘晓娟)生态相互作用对塑造生物多样性发挥关键作用。我们引入一种整合协同动力学和网络结构的方法,表明非相互作用与直接相互作用的物种在塑造共生装配中一样重要。间接影响的共同演化途径有利于在变化环境中共生伙伴缓慢而持续的性状演化,同时共同演化可以成为生态网络中塑造物种特征的主要过程。这些发现扩大了我们对相互作用驱使进化的理解。



10【生物】The prevalence of Plasmodium falciparum in sub-Saharan Africa since 1900


Robert W. Snow   et.al









(导读 郭思瑶) 疟疾的传播与气候,土地利用与人为干预有关。非洲大陆恶性疟原虫的流行程度已115年40%下降到24%,期间有快速的上升和下降,气候与人干预不能完全解释疟疾的流行律,科学家通实地调查了撒哈拉以南的非洲地区的在115年的流行状况,减少疾的行提供了宝数据。


Malaria transmission is influenced by climate, land use and deliberate interventions. Recent declines have been observed in malaria transmission. Here we show that the African continent has witnessed a long-term decline in the prevalence of Plasmodium falciparum from 40% prevalence in the period 1900–1929 to 24% prevalence in the period 2010–2015, a trend that has been interrupted by periods of rapidly increasing or decreasing transmission. The cycles and trend over the past 115 years are inconsistent with explanations in terms of climate or deliberate intervention alone. Previous global initiatives have had minor impacts on malaria transmission, and a historically unprecedented decline has been observed since 2000. However, there has been little change in the high transmission belt that covers large parts of West and Central Africa. Previous efforts to model the changing patterns of P. falciparum transmission intensity in Africa have been limited to the past 15 years1, 2 or have used maps drawn from historical expert opinions3. We provide quantitative data, from 50,424 surveys at 36,966 geocoded locations, that covers 115 years of malaria history in sub-Saharan Africa; inferring from these data to future trends, we would expect continued reductions in malaria transmission, punctuated with resurgences.



11【神经】Network control principles predict neuron function in the Caenorhabditis elegans connectome

Gang Yan,et.al



(导读 阿金)复杂系统控制原理研究提供了一套强大的数学框架来系统探索生物、社会和技术网络的结构-功能关系,但是缺乏直接的实验数据。本研究将该原理用于秀丽隐杆线虫连接组,成功预测了线虫大脑参与控制身体运动的神经元类别和单个神经元的功能,并对此进行了实验验证。本文为将此分析框架应用于更大或未知的连接组提供了基础。

Recent studies on the controllability of complex systems offer a powerful mathematical framework to systematically explore the structure–function relationship in biological, social, and technological networks. Despite theoretical advances, we lack direct experimental proof of the validity of these widely used control principles. Here we fill this gap by applying a control framework to the connectome of the nematode Caenorhabditis elegans, allowing us to predict the involvement of each C. elegans neuron in locomotor behaviours. We predict that control of the muscles or motor neurons requires 12 neuronal classes, which include neuronal groups previously implicated in locomotion by laser ablation, as well as one previously uncharacterized neuron, PDB. We validate this prediction experimentally, finding that the ablation of PDB leads to a significant loss of dorsoventral polarity in large body bends. Importantly, control principles also allow us to investigate the involvement of individual neurons within each neuronal class. For example, we predict that, within the class of DD motor neurons, only three (DD04, DD05, or DD06) should affect locomotion when ablated individually. This prediction is also confirmed; single cell ablations of DD04 or DD05 specifically affect posterior body movements, whereas ablations of DD02 or DD03 do not. Our predictions are robust to deletions of weak connections, missing connections, and rewired connections in the current connectome, indicating the potential applicability of this analytical framework to larger and less well-characterized connectomes.



12【生物】Mfsd2b is essential for the sphingosine-1-phosphate export in erythrocytes and platelets

Thiet M. Vu,   et.al



(导读 阿金)S1P是红细胞和血小板释放的重要蛋白信号,但长期以来尚未清楚其释放通路。本研究观察到S1P由主要转运蛋白超家族转运体2b(Mfsd2b)活跃输出,Mfsd2b缺失的小鼠血浆中S1P水平明显下降,对过敏性休克更敏感且红细胞形态异常。研究揭示了细胞生产S1P分子传导信号的通路,为治疗免疫和血管疾病提供新思路。

Sphingosine-1-phosphate (S1P), a potent signalling lipid secreted by red blood cells and platelets, plays numerous biologically significant roles. However, the identity of its long-sought exporter is enigmatic. Here we show that the major facilitator superfamily transporter 2b (Mfsd2b), an orphan transporter, is essential for S1P export from red blood cells and platelets. Comprehensive lipidomic analysis indicates a dramatic and specific accumulation of S1P species in Mfsd2b knockout red blood cells and platelets compared with that of wild-type controls. Consistently, biochemical assays from knockout red blood cells, platelets, and cell lines overexpressing human and mouse Mfsd2b proteins demonstrate that Mfsd2b actively exports S1P. Plasma S1P level in knockout mice is significantly reduced by 42–54% of that of wild-type level, indicating that Mfsd2b pathway contributes approximately half of the plasma S1P pool. The reduction of plasma S1P in knockout mice is insufficient to cause blood vessel leakiness, but it does render the mice more sensitive to anaphylactic shock. Stress-induced erythropoiesis significantly increased plasma S1P levels and knockout mice were sensitive to these treatments. Surprisingly, knockout mice exhibited haemolysis associated with red blood cell stomatocytes, and the haemolytic phenotype was severely increased with signs of membrane fragility under stress erythropoiesis. We show that S1P secretion by Mfsd2b is critical for red blood cell morphology. Our data reveal an unexpected physiological role of red blood cells in sphingolipid metabolism in circulation. These findings open new avenues for investigating the signalling roles of S1P derived from red blood cells and platelets.


13 【生物】Transitional basal cells at the squamous–columnar junction generate Barrett’s oesophagus

Ming Jiang,  et.al



(导读 阿金)巴雷特食管化生发生在胃食管连接处,但目前还没有一种可以完全模拟其所有特征的模型。本研究在小鼠模型的胃食管连接处鉴定出一群独特的鳞状柱状结的过渡基底祖细胞(p63+KRT5+KRT7+),胆酸反流或基因改变促进这些细胞的增殖分化,导致巴雷特食管的发展。对研发更为精确的治疗方法提供新思路。

In several organ systems, the transitional zone between different types of epithelium is a hotspot for pre-neoplastic metaplasia and malignancy, but the cells of origin for these metaplastic epithelia and subsequent malignancies remain unknown. In the case of Barrett’s oesophagus, intestinal metaplasia occurs at the gastro-oesophageal junction, where stratified squamous epithelium transitions into simple columnar cells. On the basis of a number of experimental models, several alternative cell types have been proposed as the source of this metaplasia but in all cases the evidence is inconclusive: no model completely mimics Barrett’s oesophagus in terms of the presence of intestinal goblet cells. Here we describe a transitional columnar epithelium with distinct basal progenitor cells (p63+KRT5+KRT7+) at the squamous–columnar junction of the upper gastrointestinal tract in a mouse model. We use multiple models and lineage tracing strategies to show that this squamous–columnar junction basal cell population serves as a source of progenitors for the transitional epithelium. On ectopic expression of CDX2, these transitional basal progenitors differentiate into intestinal-like epithelium (including goblet cells) and thereby reproduce Barrett’s metaplasia. A similar transitional columnar epithelium is present at the transitional zones of other mouse tissues (including the anorectal junction) as well as in the gastro-oesophageal junction in the human gut. Acid reflux-induced oesophagitis and the multilayered epithelium (believed to be a precursor of Barrett’s oesophagus) are both characterized by the expansion of the transitional basal progenitor cells. Our findings reveal a previously unidentified transitional zone in the epithelium of the upper gastrointestinal tract and provide evidence that the p63+KRT5+KRT7+ basal cells in this zone are the cells of origin for multi-layered epithelium and Barrett’s oesophagus.


14 【生物】USP7 small-molecule inhibitors interfere with ubiquitin binding


Lorna Kategaya et.al






(导读 严冰)蛋白质的泛素化修饰是真核生物细胞内调控的重要部分,而去泛素化酶往往与疾病相关,例如泛素特异性蛋白酶7(USP7)可通过肿瘤存活相关蛋白的稳定性。本文中通过核磁共振扫描为基础的筛选与结构设计,成功开发了USP7选择性抑制剂GNE-6640  GNE-6776,可以通过阻止与泛素的结合从而抑制USP7的活性。这为去泛素化酶抑制剂的研发提供了新思路。


The ubiquitin system regulates essential cellular processes in eukaryotes. Ubiquitin is ligated to substrate proteins as monomers or chains and the topology of ubiquitin modifications regulates substrate interactions with specific proteins. Thus ubiquitination directs a variety of substrate fates including proteasomal degradation1. Deubiquitinase enzymes cleave ubiquitin from substrates and are implicated in disease2; for example, ubiquitin-specific protease-7 (USP7) regulates stability of the p53 tumour suppressor and other proteins critical for tumour cell survival3. However, developing selective deubiquitinase inhibitors has been challenging4 and no co-crystal structures have been solved with small-molecule inhibitors. Here, using nuclear magnetic resonance-based screening and structure-based design, we describe the development of selective USP7 inhibitors GNE-6640 and GNE-6776. These compounds induce tumour cell death and enhance cytotoxicity with chemotherapeutic agents and targeted compounds, including PIM kinase inhibitors. Structural studies reveal that GNE-6640 and GNE-6776 non-covalently target USP7 12Å distant from the catalytic cysteine. The compounds attenuate ubiquitin binding and thus inhibit USP7 deubiquitinase activity. GNE-6640 and GNE-6776 interact with acidic residues that mediate hydrogen-bond interactions with the ubiquitin Lys48 side chain5, suggesting that USP7 preferentially interacts with and cleaves ubiquitin moieties that have free Lys48 side chains. We investigated this idea by engineering di-ubiquitin chains containing differential proximal and distal isotopic labels and measuring USP7 binding by nuclear magnetic resonance. This preferential binding protracted the depolymerization kinetics of Lys48-linked ubiquitin chains relative to Lys63-linked chains. In summary, engineering compounds that inhibit USP7 activity by attenuating ubiquitin binding suggests opportunities for developing other deubiquitinase inhibitors and may be a strategy more broadly applicable to inhibiting proteins that require ubiquitin binding for full functional activity.


15 【生物】Nucleosome–Chd1 structure and implications for chromatin remodelling


Lucas Farnung,  et.al







Chromatin-remodelling factors change nucleosome positioning and facilitate DNA transcription, replication, and repair. The conserved remodelling factor chromodomain-helicase-DNA binding protein 1(Chd1) can shift nucleosomes and induce regular nucleosome spacing. Chd1 is required for the passage of RNA polymerase II through nucleosomes and for cellular pluripotency. Chd1 contains the DNA-binding domains SANT and SLIDE, a bilobal motor domain that hydrolyses ATP, and a regulatory double chromodomain. Here we report the cryo-electron microscopy structure of Chd1 from the yeast Saccharomyces cerevisiae bound to a nucleosome at a resolution of 4.8Å. Chd1 detaches two turns of DNA from the histone octamer and binds between the two DNA gyres in a state poised for catalysis. The SANT and SLIDE domains contact detached DNA around superhelical location (SHL) 7 of the first DNA gyre. The ATPase motor binds the second DNA gyre at SHL +2 and is anchored to the N-terminal tail of histone H4, as seen in a recent nucleosome–Snf2 ATPase structure8. Comparisons with published results reveal that the double chromodomain swings towards nucleosomal DNA at SHL +1, resulting in ATPase closure. The ATPase can then promote translocation of DNA towards the nucleosome dyad, thereby loosening the first DNA gyre and remodelling the nucleosome. Translocation may involve ratcheting of the two lobes of the ATPase, which is trapped in a pre- or post-translocation state in the absence or presence, respectively, of transition state-mimicking compounds.


(导读 郭怿暄)染色质重塑因子可以改变核小体位置并促进DNA的转录、复制和修复。 Chd1是一种由DNA结合域、可以水解ATP的双叶马达结构域和具有调节功能的克罗莫结构域构成的重塑因子,在RNA Pol II通过核小体以及细胞多潜能性的决定过程中发挥重要作用。本研究解析了酵母Chd1与核小体结合的冷冻电镜结构,确定Chd1与DNA和组蛋白的相互作用方式,并揭示了在水解ATP后促进核小体转位的机制。



16【生物】Single-molecule imaging reveals receptor–G protein interactions at cell surface hot spots


Titiwat Sungkaworn,  et.al







G-protein-coupled receptors mediate the biological effects of many hormones and neurotransmitters and are important pharmacological targets. They transmit their signals to the cell interior by interacting with G proteins. However, it is unclear how receptors and G proteins meet, interact and couple. Here we analyse the concerted motion of G-protein-coupled receptors and G proteins on the plasma membrane and provide a quantitative model that reveals the key factors that underlie the high spatiotemporal complexity of their interactions. Using two-colour, single-molecule imaging we visualize interactions between individual receptors and G proteins at the surface of living cells. Under basal conditions, receptors and G proteins form activity-dependent complexes that last for around one second. Agonists specifically regulate the kinetics of receptor–G protein interactions, mainly by increasing their association rate. We find hot spots on the plasma membrane, at least partially defined by the cytoskeleton and clathrin-coated pits, in which receptors and G proteins are confined and preferentially couple. Imaging with the nanobody Nb37 suggests that signalling by G-protein-coupled receptors occurs preferentially at these hot spots. These findings shed new light on the dynamic interactions that control G-protein-coupled receptor signalling.


(导读 郭怿暄)G蛋白偶联受体参与多种激素和神经递质相关的生物效应,它们通过与G蛋白相互作用将信号传入细胞内部,是重要的药物靶点 。本研究通过双色单分子成像直接观察到活细胞表面单个G蛋白偶联受体与G蛋白的相互作用,提出定量模型,发现参与其中的重要因子以及受体激动剂的作用机理。此外实验还发现细胞膜上存在由细胞骨架和网格蛋白覆盖的G蛋白-受体偶联热点。