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Nature论文导读 1019

时间: 2017年10月30日 | 作者: admin | 来源: 未知
Nature20171019 1 【AI】Mastering the game of Go without human knowledge David Silver et.al AlphaGo Zero :自学成才的围棋大师 https://www.nature.com/nature/journal/v550/n7676/full/nature24270.html 图片来源: Nature ( 导读

Nature20171019

 

1 【AI】Mastering the game of Go without human knowledge

 

David Silver et.al

 

AlphaGo Zero:自学成才的围棋大师

 

https://www.nature.com/nature/journal/v550/n7676/full/nature24270.html

 

图片1.png 

图片来源:Nature

 

导读 郭思瑶)人工智能的长期目标就是研究出一套算法,使得机器能够通过自主学习而精通极具挑战性的领域。第一个战胜世界围棋冠军的程序AlphaGo是通过学习人类专家下棋的数据和自我博弈来进行决策练习。本研究创建了一种新的程序AlphaGo Zero,它仅依靠自我强化学习而不依赖人类的知识。AlphaGo Zero使用单个神经网络实现了无师自通,以100-0击败了之前的AlphaGo

A long-standing goal of artificial intelligence is an algorithm that learns, tabula rasa, superhuman proficiency in challenging domains. Recently, AlphaGo became the first program to defeat a world champion in the game of Go. The tree search in AlphaGo evaluated positions and selected moves using deep neural networks. These neural networks were trained by supervised learning from human expert moves, and by reinforcement learning from self-play. Here we introduce an algorithm based solely on reinforcement learning, without human data, guidance or domain knowledge beyond game rules. AlphaGo becomes its own teacher: a neural network is trained to predict AlphaGo’s own move selections and also the winner of AlphaGo’s games. This neural network improves the strength of the tree search, resulting in higher quality move selection and stronger self-play in the next iteration. Starting tabula rasa, our new program AlphaGo Zero achieved superhuman performance, winning 100–0 against the previously published, champion-defeating AlphaGo.

阅读更多:漫画告诉你这届阿尔法狗为什么这么牛

https://mp.weixin.qq.com/s/1S0CW4HxvftffhUZVya20g

 

2 【生物】BRCA1–BARD1 promotes RAD51-mediated homologous DNA pairing

 

Weixing Zhao et.al

 

BRCA1-BARD1促进RAD51介导的同源DNA配对

 

https://www.nature.com/nature/journal/v550/n7676/full/nature24060.html

 

 

The tumour suppressor complex BRCA1–BARD1 functions in the repair of DNA double-stranded breaks by homologous recombination. During this process, BRCA1–BARD1 facilitates the nucleolytic resection of DNA ends to generate a single-stranded template for the recruitment of another tumour suppressor complex, BRCA2–PALB2, and the recombinase RAD51. Here, by examining purified wild-type and mutant BRCA1–BARD1, we show that both BRCA1 and BARD1 bind DNA and interact with RAD51, and that BRCA1–BARD1 enhances the recombinase activity of RAD51. Mechanistically, BRCA1–BARD1 promotes the assembly of the synaptic complex, an essential intermediate in RAD51-mediated DNA joint formation. We provide evidence that BRCA1 and BARD1 are indispensable for RAD51 stimulation. Notably, BRCA1–BARD1 mutants with weakened RAD51 interactions show compromised DNA joint formation and impaired mediation of homologous recombination and DNA repair in cells. Our results identify a late role of BRCA1–BARD1 in homologous recombination, an attribute of the tumour suppressor complex that could be targeted in cancer therapy.

 

 

(导读 郭怿暄)抑癌因子BRCA1-BARD1复合体在利用同源重组修复DNA双链断裂中发挥重要作用。本研究通过纯化野生型和突变型BRCA1-BARD1,发现二者均结合DNA,并与重组酶RAD51相互作用,可增强其酶活性及其介导的DNA连接形成。而BRCA1-BARD1突变造成该功能受损。这一发现为开发癌症治疗靶点提供帮助。

 

 

3【生物】Human TRPML1 channel structures in open and closed conformations

 

Philip Schmiege, et.al

 

解析人类TRPML1通道在开放和关闭状态的结构

 

https://www.nature.com/nature/journal/v550/n7676/full/nature24036.html

 

 

Transient receptor potential mucolipin 1 (TRPML1) is a Ca2+-releasing cation channel that mediates the calcium signalling and homeostasis of lysosomes. Mutations in TRPML1 lead to mucolipidosis type IV, a severe lysosomal storage disorder. Here we report two electron cryo-microscopy structures of full-length human TRPML1: a 3.72-Å apo structure at pH 7.0 in the closed state, and a 3.49-Å agonist-bound structure at pH 6.0 in an open state. Several aromatic and hydrophobic residues in pore helix 1, helices S5 and S6, and helix S6 of a neighbouring subunit, form a hydrophobic cavity to house the agonist, suggesting a distinct agonist-binding site from that found in TRPV1, a TRP channel from a different subfamily. The opening of TRPML1 is associated with distinct dilations of its lower gate together with a slight structural movement of pore helix 1. Our work reveals the regulatory mechanism of TRPML channels, facilitates better understanding of TRP channel activation, and provides insights into the molecular basis of mucolipidosis type IV pathogenesis.

 

(导读 郭怿暄)TPRML1是一个介导钙离子释放、维持溶酶体稳态的阳离子通道,其突变可导致严重的IV型粘多糖症。本研究利用冷冻电镜技术分别解析了人类TRPML1在关闭和开启状态的结构,并发现该通道激动剂结合位点以及通道开启后的构象改变。这一发现揭示了TPRML通道的调节机制,为更深入地了解TRP通道激活以及IV型粘多糖病的分子病理基础提供帮助。

 

4【物理】A parts-per-billion measurement of the antiproton magnetic moment

 

C. Smorra,  et.al

 

精度高达十亿分之一量级的反质子磁矩测量

 

https://www.nature.com/nature/journal/v550/n7676/full/nature24048.html

 

(导读 阿金)对反质子磁矩的高精度测量能够检验电荷-宇称-时间(CPT)守恒。本研究精确测量了反质子的磁矩,其值为-2.792847344142μN68%置信度),精度比过去提高了350倍。该结果与质子磁矩高度吻合,进一步限制了CPT破缺效应。

 

 

Precise comparisons of the fundamental properties of matter–antimatter conjugates provide sensitive tests of charge–parity–time (CPT) invariance, which is an important symmetry that rests on basic assumptions of the standard model of particle physics. Experiments on mesons, leptons and baryons have compared different properties of matter–antimatter conjugates with fractional uncertainties at the parts-per-billion level or better. One specific quantity, however, has so far only been known to a fractional uncertainty at the parts-per-million level: the magnetic moment of the antiproton,    . The extraordinary difficulty in measuring   with high precision is caused by its intrinsic smallness; for example, it is 660 times smaller than the magnetic moment of the positron. Here we report a high-precision measurement of   in units of the nuclear magneton μN with a fractional precision of 1.5 parts per billion (68% confidence level). We use a two-particle spectroscopy method in an advanced cryogenic multi-Penning trap system. Our result   = −2.7928473441(42)μN (where the number in parentheses represents the 68% confidence interval on the last digits of the value) improves the precision of the previous best   measurement8 by a factor of approximately 350. The measured value is consistent with the proton magnetic moment9, μp=2.792847350(9)μN, and is in agreement with CPT invariance. Consequently, this measurement constrains the magnitude of certain CPT-violating effects10 to below 1.8×1024 gigaelectronvolts, and a possible splitting of the proton–antiproton magnetic moments by CPT-odd dimension-five interactions to below 6×1012 Bohr magnetons.

 

5 【物理】Solving a Higgs optimization problem with quantum annealing for machine learning

Alex Mott  et.al

利用量子退火优化希格斯玻色子的信号-背景分离

https://www.nature.com/nature/journal/v550/n7676/full/nature24047.html

(导读 阿金)机器学习方法帮助在研究人员在复杂背景中发现希格斯玻色子,但用于分离信号和背景的分类器往往会产生各种错误。本研究使用量子退火技术来优化希格斯信号分离的机器学习。研究人员基于希格斯衰变光子运动观测值构建一弱分类器,进而构建强分类器。相比传统的机器学习方法,新的分类器系统简单稳定,物理意义更加明确。有望得到更加广泛的应用

The discovery of Higgs-boson decays in a background of standard-model processes was assisted by machine learning methods. The classifiers used to separate signals such as these from background are trained using highly unerring but not completely perfect simulations of the physical processes involved, often resulting in incorrect labelling of background processes or signals (label noise) and systematic errors. Here we use quantum and classical annealing (probabilistic techniques for approximating the global maximum or minimum of a given function) to solve a Higgs-signal-versus-background machine learning optimization problem, mapped to a problem of finding the ground state of a corresponding Ising spin model. We build a set of weak classifiers based on the kinematic observables of the Higgs decay photons, which we then use to construct a strong classifier. This strong classifier is highly resilient against overtraining and against errors in the correlations of the physical observables in the training data. We show that the resulting quantum and classical annealing-based classifier systems perform comparably to the state-of-the-art machine learning methods that are currently used in particle physics. However, in contrast to these methods, the annealing-based classifiers are simple functions of directly interpretable experimental parameters with clear physical meaning. The annealer-trained classifiers use the excited states in the vicinity of the ground state and demonstrate some advantage over traditional machine learning methods for small training datasets. Given the relative simplicity of the algorithm and its robustness to error, this technique may find application in other areas of experimental particle physics, such as real-time decision making in event-selection problems and classification in neutrino physics.

 

 

6 【物理】Ion sieving in graphene oxide membranes via cationic control of interlayer spacing

 

Liang Chen,   et.al

氧化石墨烯膜通过阳离子控制层间距实现离子筛分

https://www.nature.com/nature/journal/v550/n7676/full/nature24044.html

(导读 阿金)氧化石墨烯膜可用在水溶液中进行离子分子筛分,但是层间距不固定会影响筛分性能。本研究使用K+Na+Ca2+Li+Mg2+离子表明,这些阳离子可用于精确控制氧化石墨烯膜层间距第一性原理计算和紫外吸收光谱表明,最稳定的阳离子吸附位置是氧化物基团和芳环共存的区域

Graphene oxide membranes—partially oxidized, stacked sheets of graphene1—can provide ultrathin, high-flux and energy-efficient membranes for precise ionic and molecular sieving in aqueous solution. These materials have shown potential in a variety of applications, including water desalination and purification, gas and ion separation, biosensors, proton conductors, lithium-based batteries16 and super-capacitors. Unlike the pores of carbon nanotube membranes, which have fixed sizes, the pores of graphene oxide membranes—that is, the interlayer spacing between graphene oxide sheets (a sheet is a single flake inside the membrane)—are of variable size. Furthermore, it is difficult to reduce the interlayer spacing sufficiently to exclude small ions and to maintain this spacing against the tendency of graphene oxide membranes to swell when immersed in aqueous solution. These challenges hinder the potential ion filtration applications of graphene oxide membranes. Here we demonstrate cationic control of the interlayer spacing of graphene oxide membranes with ångström precision using K+, Na+, Ca2+, Li+ or Mg2+ ions. Moreover, membrane spacings controlled by one type of cation can efficiently and selectively exclude other cations that have larger hydrated volumes. First-principles calculations and ultraviolet absorption spectroscopy reveal that the location of the most stable cation adsorption is where oxide groups and aromatic rings coexist. Previous density functional theory computations show that other cations (Fe2+, Co2+, Cu2+, Cd2+, Cr2+ and Pb2+) should have a much stronger cation–π interaction with the graphene sheet than Na+ has, suggesting that other ions could be used to produce a wider range of interlayer spacings.

 

7 【材料】Organic long persistent luminescence

Ryota Kabe & Chihaya Adachi  

长时间持续发光的有机材料

 

https://www.nature.com/nature/journal/v550/n7676/full/nature24010.html

(导读 阿金)大部分商用长余辉发光(LPL)材料的制造基于无机系统需要稀有元素以及1000摄氏度以上的高温。本研究使用两种简单的有机分子制成了OLPL系统。该系统可过标准白色LED光源激发,室温下发光时间超过一小时未来有望用于柔性涂料、生物标记等领域。

Long persistent luminescence (LPL) materials—widely commercialized as ‘glow-in-the-dark’ paints—store excitation energy in excited states that slowly release this energy as light1. At present, most LPL materials are based on an inorganic system of strontium aluminium oxide (SrAl2O4) doped with europium and dysprosium, and exhibit emission for more than ten hours2. However, this system requires rare elements and temperatures higher than 1,000 degrees Celsius during fabrication, and light scattering by SrAl2O4 powders limits the transparency of LPL paints1. Here we show that an organic LPL (OLPL) system of two simple organic molecules that is free from rare elements and easy to fabricate can generate emission that lasts for more than one hour at room temperature. Previous organic systems, which were based on two-photon ionization, required high excitation intensities and low temperatures3. By contrast, our OLPL system—which is based on emission from excited complexes (exciplexes) upon the recombination of long-lived charge-separated states—can be excited by a standard white LED light source and generate long emission even at temperatures above 100 degrees Celsius. This OLPL system is transparent, soluble, and potentially flexible and colour-tunable, opening new applications for LPL in large-area and flexible paints, biomarkers, fabrics, and windows. Moreover, the study of long-lived charge separation in this system should advance understanding of a wide variety of organic semiconductor devices4.

 

8 【神经】Social behaviour shapes hypothalamic neural ensemble representations of conspecific sex

Ryan Remedios,   et.al

社会行为塑造性别特异的下丘脑神经集成表征

https://www.nature.com/nature/journal/v550/n7676/full/nature23885.html

(导读 阿金)动物本能行为神经介导通路机制尚未清楚。本研究使用显微内窥镜观察小鼠腹内侧下丘脑(VMHvl)中雌激素受体(ESR1+)神经元活动,发现其控制交配与争斗性别特异性神经集成表征由社会经验塑造,揭示脑内深层皮质下结构的可塑性和神经动态编码。

All animals possess a repertoire of innate (or instinctive1, 2) behaviours, which can be performed without training. Whether such behaviours are mediated by anatomically distinct and/or genetically specified neural pathways remains unknown3, 4, 5. Here we report that neural representations within the mouse hypothalamus, that underlie innate social behaviours, are shaped by social experience. Oestrogen receptor 1-expressing (Esr1+) neurons in the ventrolateral subdivision of the ventromedial hypothalamus (VMHvl) control mating and fighting in rodents6, 7, 8. We used microendoscopy9 to image Esr1+ neuronal activity in the VMHvl of male mice engaged in these social behaviours. In sexually and socially experienced adult males, divergent and characteristic neural ensembles represented male versus female conspecifics. However, in inexperienced adult males, male and female intruders activated overlapping neuronal populations. Sex-specific neuronal ensembles gradually separated as the mice acquired social and sexual experience. In mice permitted to investigate but not to mount or attack conspecifics, ensemble divergence did not occur. However, 30minutes of sexual experience with a female was sufficient to promote the separation of male and female ensembles and to induce an attack response 24h later. These observations uncover an unexpected social experience-dependent component to the formation of hypothalamic neural assemblies controlling innate social behaviours. More generally, they reveal plasticity and dynamic coding in an evolutionarily ancient deep subcortical structure that is traditionally viewed as a ‘hard-wired’ system.

 

 

9 【生物】Establishment of mouse expanded potential stem cells

 

Jian Yang, et.al

建立分化潜能扩大的小鼠干细胞培养方法

 

https://www.nature.com/nature/journal/v550/n7676/full/nature24052.html

 

Mouse embryonic stem cells derived from the epiblast contribute to the somatic lineages and the germline but are excluded from the extra-embryonic tissues that are derived from the trophectoderm and the primitive endoderm upon reintroduction to the blastocyst. Here we report that cultures of expanded potential stem cells can be established from individual eight-cell blastomeres, and by direct conversion of mouse embryonic stem cells and induced pluripotent stem cells. Remarkably, a single expanded potential stem cell can contribute both to the embryo proper and to the trophectoderm lineages in a chimaera assay. Bona fide trophoblast stem cell lines and extra-embryonic endoderm stem cells can be directly derived from expanded potential stem cells in vitro. Molecular analyses of the epigenome and single-cell transcriptome reveal enrichment for blastomere-specific signature and a dynamic DNA methylome in expanded potential stem cells. The generation of mouse expanded potential stem cells highlights the feasibility of establishing expanded potential stem cells for other mammalian species.

 

(导读 郭怿暄) 小鼠ES细胞可在重新引入囊胚后为小鼠胚胎做出贡献,却无法形成胚外组织。本研究通过使用8细胞分裂球或直接转化小鼠ES或iPS细胞建立了分化潜能扩大的干细胞培养方法。单个这种细胞在嵌合体实验中即可同时参与胚胎和胚外组织的分化。这一培养方法为分化潜能扩大的干细胞培养应用于其他物种带来可能。

 

 

10 【神经】Radically truncated MeCP2 rescues Rett syndrome-like neurological defects

 

Rebekah Tillotson,et.al

被大部分删除的MeCP2蛋白可反转Rett综合征样神经缺陷

https://www.nature.com/nature/journal/v550/n7676/full/nature24058.html

 

Heterozygous mutations in the X-linked MECP2 gene cause the neurological disorder Rett syndrome. The methyl-CpG-binding protein 2 (MeCP2) protein is an epigenetic reader whose binding to chromatin primarily depends on 5-methylcytosine. Functionally, MeCP2 has been implicated in several cellular processes on the basis of its reported interaction with more than 40 binding partners, including transcriptional co-repressors (for example, the NCoR/SMRT complex), transcriptional activators, RNA, chromatin remodellers, microRNA-processing proteins and splicing factors. Accordingly, MeCP2 has been cast as a multi-functional hub that integrates diverse processes that are essential in mature neurons. At odds with the concept of broad functionality, missense mutations that cause Rett syndrome are concentrated in two discrete clusters coinciding with interaction sites for partner macromolecules: the methyl-CpG binding domain and the NCoR/SMRT interaction domain. Here we test the hypothesis that the single dominant function of MeCP2 is to physically connect DNA with the NCoR/SMRT complex, by removing almost all amino-acid sequences except the methyl-CpG binding and NCoR/SMRT interaction domains. We find that mice expressing truncated MeCP2 lacking both the N- and C-terminal regions (approximately half of the native protein) are phenotypically near-normal; and those expressing a minimal MeCP2 additionally lacking a central domain survive for over one year with only mild symptoms. This minimal protein is able to prevent or reverse neurological symptoms when introduced into MeCP2-deficient mice by genetic activation or virus-mediated delivery to the brain. Thus, despite evolutionary conservation of the entire MeCP2 protein sequence, the DNA and co-repressor binding domains alone are sufficient to avoid Rett syndrome-like defects and may therefore have therapeutic utility.

 

(导读 郭怿暄)位于X染色体上的MeCP2作为一个可与DNA及多种因子结合的枢纽对成熟神经元非常重要。该基因发生杂合突变可导致Rett综合征,突变集中在其甲基化CpG结合域和NCoR/SMRT结合域。本研究发现仅保留这两个结构域的MeCP2蛋白可以预防或反转该基因缺乏小鼠的神经症状,去除该蛋白其余大段区域小鼠表型仍接近正常。这提示这两个重要结构域具有药物开发前景。

 

 

11 【生物】Cytoplasmic chromatin triggers inflammation in senescence and cancer

 

Zhixun Dou,,et.al

衰老和癌症中细胞质染色质诱导炎症反应发生

 

https://www.nature.com/nature/journal/v550/n7676/full/nature24050.html

 

Chromatin is traditionally viewed as a nuclear entity that regulates gene expression and silencing. However, we recently discovered the presence of cytoplasmic chromatin fragments that pinch off from intact nuclei of primary cells during senescence, a form of terminal cell-cycle arrest associated with pro-inflammatory responses. The functional significance of chromatin in the cytoplasm is unclear. Here we show that cytoplasmic chromatin activates the innate immunity cytosolic DNA-sensing cGAS–STING (cyclic GMP–AMP synthase linked to stimulator of interferon genes) pathway, leading both to short-term inflammation to restrain activated oncogenes and to chronic inflammation that associates with tissue destruction and cancer. The cytoplasmic chromatin–cGAS–STING pathway promotes the senescence-associated secretory phenotype in primary human cells and in mice. Mice deficient in STING show impaired immuno-surveillance of oncogenic RAS and reduced tissue inflammation upon ionizing radiation. Furthermore, this pathway is activated in cancer cells, and correlates with pro-inflammatory gene expression in human cancers. Overall, our findings indicate that genomic DNA serves as a reservoir to initiate a pro-inflammatory pathway in the cytoplasm in senescence and cancer. Targeting the cytoplasmic chromatin-mediated pathway may hold promise in treating inflammation-related disorders.

 

(导读 郭怿暄)细胞衰老时染色质片段会被挤出细胞核存在于细胞质中,但其功能尚不清楚。本研究发现细胞质染色质可激活cGAS-STING通路,使细胞出现衰老相关分泌表型,引起短期和慢性炎症反应。这一通路在癌症细胞中激活,并与促炎症基因表达相关。这提示着眼于细胞质染色质介导的通路有助于治疗与之相关的炎症问题。

 

 

12 【生物】Enhanced proofreading governs CRISPR–Cas9 targeting accuracy

 

Janice S. Chen, ,et.al

加强校对功能控制CRISPR-Cas9的定位精度

 

 

https://www.nature.com/nature/journal/v550/n7676/full/nature24268.html

 

图片2.png 

图片来源:Nature

 

(导读 郭思瑶)酿脓链球菌中RNA向的CRISPR–Cas9核酸酶(SpCas9)已被广泛用于基因组编辑,但其靶标识别机制和保真度提高的方法尚不清楚。科研人员发现Cas9的REC3结构域可互补性识别靶标,控制HNH核酸酶,从而调控整体的催化能力。科研人据此设计了一种新的高准确度Cas9变体HypaCas9,这为平衡靶标识别能力与核酸活性提供了新模型。

 

 

The RNA-guided CRISPR–Cas9 nuclease from Streptococcus pyogenes (SpCas9) has been widely repurposed for genome editing. High-fidelity (SpCas9-HF1) and enhanced specificity (eSpCas9(1.1)) variants exhibit substantially reduced off-target cleavage in human cells, but the mechanism of target discrimination and the potential to further improve fidelity are unknown. Here, using single-molecule Förster resonance energy transfer experiments, we show that both SpCas9-HF1 and eSpCas9(1.1) are trapped in an inactive state10 when bound to mismatched targets. We find that a non-catalytic domain within Cas9, REC3, recognizes target complementarity and governs the HNH nuclease to regulate overall catalytic competence. Exploiting this observation, we design a new hyper-accurate Cas9 variant (HypaCas9) that demonstrates high genome-wide specificity without compromising on-target activity in human cells. These results offer a more comprehensive model to rationalize and modify the balance between target recognition and nuclease activation for precision genome editing.

 

13 【生物】Cryo-electron microscopy structure of the lysosomal calcium-permeable channel TRPML3

 

Marscha Hirschi, ,et.al

 

溶酶体钙渗透通道TRPML3冷冻电镜结构

 

https://www.nature.com/nature/journal/v550/n7676/full/nature24055.html

 

The modulation of ion channel activity by lipids is increasingly recognized as a fundamental component of cellular signalling. The transient receptor potential mucolipin (TRPML) channel family belongs to the TRP superfamily and is composed of three members: TRPML1–TRPML3. TRPMLs are the major Ca2+-permeable channels on late endosomes and lysosomes (LEL). They regulate the release of Ca2+ from organelles, which is important for various physiological processes, including organelle trafficking and fusion. Loss-of-function mutations in the MCOLN1 gene, which encodes TRPML1, cause the neurodegenerative lysosomal storage disorder mucolipidosis type IV, and a gain-of-function mutation (Ala419Pro) in TRPML3 gives rise to the varitint–waddler (Va) mouse phenotype. Notably, TRPML channels are activated by the low-abundance and LEL-enriched signalling lipid phosphatidylinositol-3,5-bisphosphate (PtdIns(3,5)P2), whereas other phosphoinositides such as PtdIns(4,5)P2, which is enriched in plasma membranes, inhibit TRPMLs. Conserved basic residues at the N terminus of the channel are important for activation by PtdIns(3,5)P2 and inhibition by PtdIns(4,5)P2. However, owing to a lack of structural information, the mechanism by which TRPML channels recognize PtdIns(3,5)P2 and increase their Ca2+ conductance remains unclear. Here we present the cryo-electron microscopy (cryo-EM) structure of a full-length TRPML3 channel from the common marmoset (Callithrix jacchus) at an overall resolution of 2.9Å. Our structure reveals not only the molecular basis of ion conduction but also the unique architecture of TRPMLs, wherein the voltage sensor-like domain is linked to the pore via a cytosolic domain that we term the mucolipin domain. Combined with functional studies, these data suggest that the mucolipin domain is responsible for PtdIns(3,5)P2 binding and subsequent channel activation, and that it acts as a ‘gating pulley’ for lipid-dependent TRPML gating.

 

(导读 郭怿暄)TRPMLs是存在于晚期内体和溶酶体(LEL)的主要钙离子通道,对细胞器运输和融合十分重要。这类通道可被富集于LEL的低浓度信号脂质PtdIns(3,5)P2激活,但其它存在于细胞膜上的磷酸肌醇则起抑制作用。本研究利用冷冻电镜技术解析TRPML3结构,发现其独特的粘脂蛋白结构域,揭示了该结构域结合PtdIns(3,5)P2并使离子通道激活的机制。

 

 

14 【生物】Structure of mammalian endolysosomal TRPML1 channel in nanodiscs

 

Qingfeng Chen, ,et.al

 

解析哺乳动物纳米盘中内溶酶体TRPML1通道的结构

 

https://www.nature.com/nature/journal/v550/n7676/full/nature24035.html

 

 

 

Transient receptor potential mucolipin 1 (TRPML1) is a cation channel located within endosomal and lysosomal membranes. Ubiquitously expressed in mammalian cells, its loss-of-function mutations are the direct cause of type IV mucolipidosis, an autosomal recessive lysosomal storage disease. Here we present the single-particle electron cryo-microscopy structure of the mouse TRPML1 channel embedded in nanodiscs. Combined with mutagenesis analysis, the TRPML1 structure reveals that phosphatidylinositol-3,5-bisphosphate (PtdIns(3,5)P2) binds to the N terminus of the channel—distal from the pore—and the helix–turn–helix extension between segments S2 and S3 probably couples ligand binding to pore opening. The tightly packed selectivity filter contains multiple ion-binding sites, and the conserved acidic residues form the luminal Ca2+-blocking site that confers luminal pH and Ca2+ modulation on channel conductance. A luminal linker domain forms a fenestrated canopy atop the channel, providing several luminal ion passages to the pore and creating a negative electrostatic trap, with a preference for divalent cations, at the luminal entrance. The structure also reveals two equally distributed S4–S5 linker conformations in the closed channel, suggesting an S4–S5 linker-mediated PtdInsP2 gating mechanism among TRPML channels.

 

(导读 郭怿暄)TRPML1是广泛表达于哺乳动物细胞胞内体和溶酶体膜上的阳离子通道,其功能缺失型突变是导致IV型粘多糖症的直接原因。本研究解析嵌入纳米盘上小鼠TRPML1通道的单分子冷冻电子显微结构,发现PtdIns(3,5)P2结合位点、孔道开闭机制,以及该通道对于离子电荷性偏好选择的结构基础。