目次

Editorials

米政府は、地球観測をどのように進めるかについて、明確な戦略を立てる必要がある。

Plan for the future p.5

The White House urgently needs to set out a clear plan for how it intends to monitor the state of Earth.

doi: 10.1038/497005a

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遺伝子組換え作物の研究は、産業界とは離れた外部で行うべきだ。

Fields of gold p.5

Research on transgenic crops must be done outside industry if it is to fulfil its early promise.

doi: 10.1038/497005b

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英国の名誉毀損法の改正は、全て期待どおりではないにしても、喜ばしい勝利だ。

Freed speech p.6

The reform of English libel law is a victory, even if it doesn’t achieve everything that was hoped.

doi: 10.1038/497006a

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News

世界の二酸化炭素レベルが、来月にも400 ppmという懸念すべき値に。

Global carbon dioxide levels near worrisome milestone p.13

Concentrations of greenhouse gas will soon surpass 400 parts per million at sentinel spot.

doi: 10.1038/497013a

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鳥インフルエンザ研究の競争激化で、中国の研究者たちからクレジットをめぐり怒りの声が。

Flu papers spark row over credit for data p.14

Rush to publish on H7N9 avian flu upsets Chinese scientists.

doi: 10.1038/497014a

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知能プライミング効果に関する著名な論文が再現できず、社会心理学界に動揺が。

Disputed results a fresh blow for social psychology p.16

Failure to replicate intelligence-priming effects ignites row in research community.

doi: 10.1038/497016a

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FDAによる長い審査を経て、遺伝子組換えサケの認可が間近に。

Transgenic salmon nears approval p.17

Slow US regulatory process highlights hurdles of getting engineered food animals to dinner tables.

doi: 10.1038/497017a

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C型肝炎の標的薬の第3相試験で、有望な結果が。

Targeted drugs to tackle hepatitis C p.18

But experts debate US screening recommendations.

doi: 10.1038/497018a

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長く東南アジアで活動してきた臨床医のJeremy Farrarが、ウェルカムトラストの理事長に。

Clinician to head Wellcome Trust p.19

Jeremy Farrar to lead one of world’s largest research charities.

doi: 10.1038/497019a

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News Features

色あせた期待

Plant biotechnology: Tarnished promise p.21

遺伝子組換え作物が巻き起こす、興奮と嫌悪の物語を掘り下げる。

doi: 10.1038/497021a

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遺伝子組換え作物の数の物語

GM crops: A story in numbers p.22

初めて市場に出てから約20年たつ遺伝子組換え作物の現状を数字で見る。

doi: 10.1038/497022a

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遺伝子組換え作物を厳しく検討

Case studies: A hard look at GM crops p.24

トランスジェニック神話の誤りを暴く。

doi: 10.1038/497024a

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新しい品種

Transgenics: A new breed p.27

商品化に向けて進んでいる新世代の遺伝子組換え作物は、「フランケンシュタイン食品」への恐れを和らげるかもしれない。

doi: 10.1038/497027a

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News & Views

神経科学:認知地図による航路決定

Neuroscience: Navigation with a cognitive map p.42

海馬の場所細胞は、動物の空間世界についての情報をコードしている。ラットでは、これと同じ細胞が、行動開始前にこれからの行程を次々に予想することが、今回明らかにされた。

doi: 10.1038/nature12095

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地球科学:同一なものに見られる小さな相異

Earth science: Small differences in sameness p.43

新たな証拠から地球のケイ酸塩成分の鉄同位体組成は、以前に考えられていたのは違って、高圧での地球核形成あるいは宇宙空間への物質の喪失のどちらをも反映していないことがわかった。

doi: 10.1038/497043a

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構造生物学:活性化されたアレスチンの結晶化

Structural biology: Active arrestin proteins crystallized p.45

タンパク質のアレスチンは、広く存在するGタンパク質共役受容体によって開始される細胞内シグナル伝達カスケードを調節している。2種類のアレスチンが、活性化の際に同じような構造変化を起こしていることが、結晶構造の研究から明らかになった。

doi: 10.1038/nature12096

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固体物理学:シリコン中の単一スピンを調べる

Solid-state physics: Single spins in silicon see the light p.46

微小なシリコントランジスター中にある1個のエルビウム原子中のスピン状態がレーザー光を使って調べられた。こうして得られた知見はハイブリッドなスピン–光子量子計算アーキテクチャーに向かう道を開くものだ。

doi: 10.1038/497046a

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光学デバイス:昆虫の目で世界を見る

Optical devices: Seeing the world through an insect's eyes p.47

エレクトロニクスと弾性材料との巧妙な組み合わせを使って、昆虫の目によく似た小型の視覚センサーが構築された。このデバイスは、ごく小型の無人航空機で使われる自律航法につながる道を開く。

doi: 10.1038/497047a

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分子生物学:目標は手段を正当化する

Molecular biology: The ends justify the means p.48

酵母ゲノムの解析から、開始部分と終止部分の塩基配列が異なる多様なRNA分子を、個々の遺伝子が産生していることが明らかになった。このような転写産物に見られる変動は、遺伝子調節機構の多様性を反映している。

doi: 10.1038/nature12098

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生化学:脱ユビキチン化段階を制御する酸化反応

Biochemistry: Oxidation controls the DUB step p.49

アミノ酸残基の可逆的な酸化は、細胞内酵素の活性を直接調節することが可能である。この原理が脱ユビキチン化酵素にも当てはまることが今回明らかになり、これが細胞のシグナル伝達とタンパク質の代謝回転に関係していることが示唆された。

doi: 10.1038/497049a

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Perspectives

複雑ネットワーク:グローバルにネットワーク化されたリスクとその対処法

Globally networked risks and how to respond p.51

Today’s strongly connected, global networks have produced highly interdependent systems that we do not understand and cannot control well. These systems are vulnerable to failure at all scales, posing serious threats to society, even when external shocks are absent. As the complexity and interaction strengths in our networked world increase, man-made systems can become unstable, creating uncontrollable situations even when decision-makers are well-skilled, have all data and technology at their disposal, and do their best. To make these systems manageable, a fundamental redesign is needed. A ‘Global Systems Science’ might create the required knowledge and paradigm shift in thinking.

doi: 10.1038/nature12047

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植物科学:持続可能な食糧生産のために膜輸送体を用いて作物を改良する

Using membrane transporters to improve crops for sustainable food production p.60

With the global population predicted to grow by at least 25 per cent by 2050, the need for sustainable production of nutritious foods is critical for human and environmental health. Recent advances show that specialized plant membrane transporters can be used to enhance yields of staple crops, increase nutrient content and increase resistance to key stresses, including salinity, pathogens and aluminium toxicity, which in turn could expand available arable land.

doi: 10.1038/nature11909

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Articles

がん:子宮内膜がんの総合的なゲノム特性解析

Integrated genomic characterization of endometrial carcinoma OPEN p.67

An integrative genomic analysis of several hundred endometrial carcinomas shows that a minority of tumour samples carry copy number alterations or TP53 mutations and many contain key cancer-related gene mutations, such as those involved in canonical pathways and chromatin remodelling; a reclassification of endometrial tumours into four distinct types is proposed, which may have an effect on patient treatment regimes.

doi: 10.1038/nature12113

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神経科学:海馬場所細胞の順序立って起こる発火は記憶したゴールへの将来の経路を描き出す

Hippocampal place-cell sequences depict future paths to remembered goals p.74

It is known that compressed sequences of hippocampal place cells can ‘replay’ previous navigational trajectories in linearly constrained mazes; here, rat place-cell sequences representing two-dimensional spatial trajectories were observed before navigational decisions, and predicted the immediate navigational path.

doi: 10.1038/nature12112

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構造生物学:ヒトおよびショウジョウバエの80Sリボソームの構造

Structures of the human and Drosophila 80S ribosome p.80

High-resolution cryo-EM density maps are used to present the structures of Drosophila and human 80S ribosomes in complex with eEF2, E-site transfer RNA and Stm1-like proteins, and reveal the presence of two additional structural layers in the ribosomes of metazoan eukaryotes.

doi: 10.1038/nature12104

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Letters

量子物理学:3 m離れた固体キュービット間の前触れ量子もつれ

Heralded entanglement between solid-state qubits separated by three metres p.86

Quantum entanglement between spatially separated objects is one of the most intriguing phenomena in physics. The outcomes of independent measurements on entangled objects show correlations that cannot be explained by classical physics. As well as being of fundamental interest, entanglement is a unique resource for quantum information processing and communication. Entangled quantum bits (qubits) can be used to share private information or implement quantum logical gates. Such capabilities are particularly useful when the entangled qubits are spatially separated, providing the opportunity to create highly connected quantum networks or extend quantum cryptography to long distances. Here we report entanglement of two electron spin qubits in diamond with a spatial separation of three metres. We establish this entanglement using a robust protocol based on creation of spin–photon entanglement at each location and a subsequent joint measurement of the photons. Detection of the photons heralds the projection of the spin qubits onto an entangled state. We verify the resulting non-local quantum correlations by performing single-shot readout on the qubits in different bases. The long-distance entanglement reported here can be combined with recently achieved initialization, readout and entanglement operations on local long-lived nuclear spin registers, paving the way for deterministic long-distance teleportation, quantum repeaters and extended quantum networks.

doi: 10.1038/nature12016

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量子物理学:シリコン中の単一エルビウムイオンの光アドレッシング

Optical addressing of an individual erbium ion in silicon p.91

The detection of electron spins associated with single defects in solids is a critical operation for a range of quantum information and measurement applications under development. So far, it has been accomplished for only two defect centres in crystalline solids: phosphorus dopants in silicon, for which electrical read-out based on a single-electron transistor is used, and nitrogen–vacancy centres in diamond, for which optical read-out is used. A spin read-out fidelity of about 90 per cent has been demonstrated with both electrical read-out and optical read-out; however, the thermal limitations of the former and the poor photon collection efficiency of the latter make it difficult to achieve the higher fidelities required for quantum information applications. Here we demonstrate a hybrid approach in which optical excitation is used to change the charge state (conditional on its spin state) of an erbium defect centre in a silicon-based single-electron transistor, and this change is then detected electrically. The high spectral resolution of the optical frequency-addressing step overcomes the thermal broadening limitation of the previous electrical read-out scheme, and the charge-sensing step avoids the difficulties of efficient photon collection. This approach could lead to new architectures for quantum information processing devices and could drastically increase the range of defect centres that can be exploited. Furthermore, the efficient electrical detection of the optical excitation of single sites in silicon represents a significant step towards developing interconnects between optical-based quantum computing and silicon technologies.

doi: 10.1038/nature12081

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工学:節足動物の眼から着想を得て設計されたデジタルカメラ

Digital cameras with designs inspired by the arthropod eye p.95

In arthropods, evolution has created a remarkably sophisticated class of imaging systems, with a wide-angle field of view, low aberrations, high acuity to motion and an infinite depth of field. A challenge in building digital cameras with the hemispherical, compound apposition layouts of arthropod eyes is that essential design requirements cannot be met with existing planar sensor technologies or conventional optics. Here we present materials, mechanics and integration schemes that afford scalable pathways to working, arthropod-inspired cameras with nearly full hemispherical shapes (about 160 degrees). Their surfaces are densely populated by imaging elements (artificial ommatidia), which are comparable in number (180) to those of the eyes of fire ants (Solenopsis fugax) and bark beetles (Hylastes nigrinus). The devices combine elastomeric compound optical elements with deformable arrays of thin silicon photodetectors into integrated sheets that can be elastically transformed from the planar geometries in which they are fabricated to hemispherical shapes for integration into apposition cameras. Our imaging results and quantitative ray-tracing-based simulations illustrate key features of operation. These general strategies seem to be applicable to other compound eye devices, such as those inspired by moths and lacewings (refracting superposition eyes), lobster and shrimp (reflecting superposition eyes), and houseflies (neural superposition eyes).

doi: 10.1038/nature12083

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地球:まれな硫黄同位体異常の堆積による長期再循環

Long-term sedimentary recycling of rare sulphur isotope anomalies p.100

The accumulation of substantial quantities of O2 in the atmosphere has come to control the chemistry and ecological structure of Earth’s surface. Non-mass-dependent (NMD) sulphur isotope anomalies in the rock record are the central tool used to reconstruct the redox history of the early atmosphere. The generation and initial delivery of these anomalies to marine sediments requires low partial pressures of atmospheric O2 (; refs 2, 3), and the disappearance of NMD anomalies from the rock record 2.32 billion years ago is thought to have signalled a departure from persistently low atmospheric oxygen levels (less than about 10−5 times the present atmospheric level) during approximately the first two billion years of Earth’s history. Here we present a model study designed to describe the long-term surface recycling of crustal NMD anomalies, and show that the record of this geochemical signal is likely to display a ‘crustal memory effect’ following increases in atmospheric above this threshold. Once NMD anomalies have been buried in the upper crust they are extremely resistant to removal, and can be erased only through successive cycles of weathering, dilution and burial on an oxygenated Earth surface. This recycling results in the residual incorporation of NMD anomalies into the sedimentary record long after synchronous atmospheric generation of the isotopic signal has ceased, with dynamic and measurable signals probably surviving for as long as 10–100 million years subsequent to an increase in atmospheric to more than 10−5 times the present atmospheric level. Our results can reconcile geochemical evidence for oxygen production and transient accumulation with the maintenance of NMD anomalies on the early Earth, and suggest that future work should investigate the notion that temporally continuous generation of new NMD sulphur isotope anomalies in the atmosphere was likely to have ceased long before their ultimate disappearance from the rock record.

doi: 10.1038/nature12021

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進化:主竜類の鳥類系統における体型の進化と運動生体力学的特性の結びつき

Linking the evolution of body shape and locomotor biomechanics in bird-line archosaurs p.104

Locomotion in living birds (Neornithes) has two remarkable features: feather-assisted flight, and the use of unusually crouched hindlimbs for bipedal support and movement. When and how these defining functional traits evolved remains controversial. However, the advent of computer modelling approaches and the discoveries of exceptionally preserved key specimens now make it possible to use quantitative data on whole-body morphology to address the biomechanics underlying this issue. Here we use digital body reconstructions to quantify evolutionary trends in locomotor biomechanics (whole-body proportions and centre-of-mass position) across the clade Archosauria. We use three-dimensional digital reconstruction to estimate body shape from skeletal dimensions for 17 archosaurs along the ancestral bird line, including the exceptionally preserved, feathered taxa Microraptor, Archaeopteryx, Pengornis and Yixianornis, which represent key stages in the evolution of the avian body plan. Rather than a discrete transition from more-upright postures in the basal-most birds (Avialae) and their immediate outgroup deinonychosauria, our results support hypotheses of a gradual, stepwise acquisition of more-crouched limb postures across much of theropod evolution, although we find evidence of an accelerated change within the clade Maniraptora (birds and their closest relatives, such as deinonychosaurs). In addition, whereas reduction of the tail is widely accepted to be the primary morphological factor correlated with centre-of-mass position and, hence, evolution of hindlimb posture, we instead find that enlargement of the pectoral limb and several associated trends have a much stronger influence. Intriguingly, our support for the onset of accelerated morpho-functional trends within Maniraptora is closely correlated with the evolution of flight. Because we find that the evolution of enlarged forelimbs is strongly linked, via whole-body centre of mass, to hindlimb function during terrestrial locomotion, we suggest that the evolution of avian flight is linked to anatomical novelties in the pelvic limb as well as the pectoral.

doi: 10.1038/nature12059

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がん:がん治療に対する獲得抵抗性についての血漿DNA塩基配列解読による非侵襲的解析

Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA p.108

Cancers acquire resistance to systemic treatment as a result of clonal evolution and selection. Repeat biopsies to study genomic evolution as a result of therapy are difficult, invasive and may be confounded by intra-tumour heterogeneity. Recent studies have shown that genomic alterations in solid cancers can be characterized by massively parallel sequencing of circulating cell-free tumour DNA released from cancer cells into plasma, representing a non-invasive liquid biopsy. Here we report sequencing of cancer exomes in serial plasma samples to track genomic evolution of metastatic cancers in response to therapy. Six patients with advanced breast, ovarian and lung cancers were followed over 1–2 years. For each case, exome sequencing was performed on 2–5 plasma samples (19 in total) spanning multiple courses of treatment, at selected time points when the allele fraction of tumour mutations in plasma was high, allowing improved sensitivity. For two cases, synchronous biopsies were also analysed, confirming genome-wide representation of the tumour genome in plasma. Quantification of allele fractions in plasma identified increased representation of mutant alleles in association with emergence of therapy resistance. These included an activating mutation in PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha) following treatment with paclitaxel; a truncating mutation in RB1 (retinoblastoma 1) following treatment with cisplatin; a truncating mutation in MED1 (mediator complex subunit 1) following treatment with tamoxifen and trastuzumab, and following subsequent treatment with lapatinib, a splicing mutation in GAS6 (growth arrest-specific 6) in the same patient; and a resistance-conferring mutation in EGFR (epidermal growth factor receptor; T790M) following treatment with gefitinib. These results establish proof of principle that exome-wide analysis of circulating tumour DNA could complement current invasive biopsy approaches to identify mutations associated with acquired drug resistance in advanced cancers. Serial analysis of cancer genomes in plasma constitutes a new paradigm for the study of clonal evolution in human cancers.

doi: 10.1038/nature12065

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神経科学:ショウジョウバエのキノコ体に見られる嗅覚入力のランダムな収束

Random convergence of olfactory inputs in the Drosophila mushroom body p.113

The mushroom body in the fruitfly Drosophila melanogaster is an associative brain centre that translates odour representations into learned behavioural responses. Kenyon cells, the intrinsic neurons of the mushroom body, integrate input from olfactory glomeruli to encode odours as sparse distributed patterns of neural activity. We have developed anatomic tracing techniques to identify the glomerular origin of the inputs that converge onto 200 individual Kenyon cells. Here we show that each Kenyon cell integrates input from a different and apparently random combination of glomeruli. The glomerular inputs to individual Kenyon cells show no discernible organization with respect to their odour tuning, anatomic features or developmental origins. Moreover, different classes of Kenyon cells do not seem to preferentially integrate inputs from specific combinations of glomeruli. This organization of glomerular connections to the mushroom body could allow the fly to contextualize novel sensory experiences, a feature consistent with the role of this brain centre in mediating learned olfactory associations and behaviours.

doi: 10.1038/nature12063

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細胞:オーロラBキナーゼによる張力の感知はサバイビンによるセントロメア局在に依存しない

Tension sensing by Aurora B kinase is independent of survivin-based centromere localization p.118

Accurate segregation of the replicated genome requires chromosome biorientation on the spindle. Biorientation is ensured by Aurora B kinase (Ipl1), a member of the four-subunit chromosomal passenger complex (CPC). Localization of the CPC to the inner centromere is central to the current model for how tension ensures chromosome biorientation: kinetochore–spindle attachments that are not under tension remain close to the inner centromere and are destabilized by Aurora B phosphorylation, whereas kinetochores under tension are pulled away from the influence of Aurora B, stabilizing their microtubule attachments. Here we show that an engineered truncation of the Sli15 (known as INCENP in humans) subunit of budding yeast CPC that eliminates association with the inner centromere nevertheless supports proper chromosome segregation during both mitosis and meiosis. Truncated Sli15 suppresses the deletion phenotypes of the inner-centromere-targeting proteins survivin (Bir1), borealin (Nbl1), Bub1 and Sgo1 (ref. 6). Unlike wild-type Sli15, truncated Sli15 localizes to pre-anaphase spindle microtubules. Premature targeting of full-length Sli15 to microtubules by preventing Cdk1 (also known as Cdc28) phosphorylation also suppresses the inviability of Bir1 deletion. These results suggest that activation of Aurora B kinase by clustering either on chromatin or on microtubules is sufficient for chromosome biorientation.

doi: 10.1038/nature12057

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遺伝学:CXXCドメインタンパク質IDAXによるTET2発現と5-メチルシトシン酸化の調節

Modulation of TET2 expression and 5-methylcytosine oxidation by the CXXC domain protein IDAX p.122

TET (ten-eleven-translocation) proteins are Fe(ii)- and α-ketoglutarate-dependent dioxygenases that modify the methylation status of DNA by successively oxidizing 5-methylcytosine to 5-hydroxymethylcytosine, 5-formylcytosine and 5-carboxycytosine, potential intermediates in the active erasure of DNA-methylation marks. Here we show that IDAX (also known as CXXC4), a reported inhibitor of Wnt signalling that has been implicated in malignant renal cell carcinoma and colonic villous adenoma, regulates TET2 protein expression. IDAX was originally encoded within an ancestral TET2 gene that underwent a chromosomal gene inversion during evolution, thus separating the TET2 CXXC domain from the catalytic domain. The IDAX CXXC domain binds DNA sequences containing unmethylated CpG dinucleotides, localizes to promoters and CpG islands in genomic DNA and interacts directly with the catalytic domain of TET2. Unexpectedly, IDAX expression results in caspase activation and TET2 protein downregulation, in a manner that depends on DNA binding through the IDAX CXXC domain, suggesting that IDAX recruits TET2 to DNA before degradation. IDAX depletion prevents TET2 downregulation in differentiating mouse embryonic stem cells, and short hairpin RNA against IDAX increases TET2 protein expression in the human monocytic cell line U937. Notably, we find that the expression and activity of TET3 is also regulated through its CXXC domain. Taken together, these results establish the separate and linked CXXC domains of TET2 and TET3, respectively, as previously unknown regulators of caspase activation and TET enzymatic activity.

doi: 10.1038/nature12052

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細胞:アイソフォームのプロファイリングにより明らかにされた転写の大規模な不均一性

Extensive transcriptional heterogeneity revealed by isoform profiling p.127

Transcript function is determined by sequence elements arranged on an individual RNA molecule. Variation in transcripts can affect messenger RNA stability, localization and translation, or produce truncated proteins that differ in localization or function. Given the existence of overlapping, variable transcript isoforms, determining the functional impact of the transcriptome requires identification of full-length transcripts, rather than just the genomic regions that are transcribed. Here, by jointly determining both transcript ends for millions of RNA molecules, we reveal an extensive layer of isoform diversity previously hidden among overlapping RNA molecules. Variation in transcript boundaries seems to be the rule rather than the exception, even within a single population of yeast cells. Over 26 major transcript isoforms per protein-coding gene were expressed in yeast. Hundreds of short coding RNAs and truncated versions of proteins are concomitantly encoded by alternative transcript isoforms, increasing protein diversity. In addition, approximately 70% of genes express alternative isoforms that vary in post-transcriptional regulatory elements, and tandem genes frequently produce overlapping or even bicistronic transcripts. This extensive transcript diversity is generated by a relatively simple eukaryotic genome with limited splicing, and within a genetically homogeneous population of cells. Our findings have implications for genome compaction, evolution and phenotypic diversity between single cells. These data also indicate that isoform diversity as well as RNA abundance should be considered when assessing the functional repertoire of genomes.

doi: 10.1038/nature12121

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生化学:細菌によるメタンの好気的産生の触媒機構

The catalytic mechanism for aerobic formation of methane by bacteria p.132

Methane is a potent greenhouse gas that is produced in significant quantities by aerobic marine organisms. These bacteria apparently catalyse the formation of methane through the cleavage of the highly unreactive carbon–phosphorus bond in methyl phosphonate (MPn), but the biological or terrestrial source of this compound is unclear. However, the ocean-dwelling bacterium Nitrosopumilus maritimus catalyses the biosynthesis of MPn from 2-hydroxyethyl phosphonate and the bacterial C–P lyase complex is known to convert MPn to methane. In addition to MPn, the bacterial C–P lyase complex catalyses C–P bond cleavage of many alkyl phosphonates when the environmental concentration of phosphate is low. PhnJ from the C–P lyase complex catalyses an unprecedented C–P bond cleavage reaction of ribose-1-phosphonate-5-phosphate to methane and ribose-1,2-cyclic-phosphate-5-phosphate. This reaction requires a redox-active [4Fe–4S]-cluster and S-adenosyl-l-methionine, which is reductively cleaved to l-methionine and 5′-deoxyadenosine. Here we show that PhnJ is a novel radical S-adenosyl-l-methionine enzyme that catalyses C–P bond cleavage through the initial formation of a 5′-deoxyadenosyl radical and two protein-based radicals localized at Gly 32 and Cys 272. During this transformation, the pro-R hydrogen from Gly 32 is transferred to the 5′-deoxyadenosyl radical to form 5′-deoxyadenosine and the pro-S hydrogen is transferred to the radical intermediate that ultimately generates methane. A comprehensive reaction mechanism is proposed for cleavage of the C–P bond by the C–P lyase complex that uses a covalent thiophosphate intermediate for methane and phosphate formation.

doi: 10.1038/nature12061

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構造生物学:Gタンパク質共役受容体由来のリン酸化ペプチドに結合した活性なβアレスチン1の構造

Structure of active β-arrestin-1 bound to a G-protein-coupled receptor phosphopeptide p.137

The functions of G-protein-coupled receptors (GPCRs) are primarily mediated and modulated by three families of proteins: the heterotrimeric G proteins, the G-protein-coupled receptor kinases (GRKs) and the arrestins. G proteins mediate activation of second-messenger-generating enzymes and other effectors, GRKs phosphorylate activated receptors, and arrestins subsequently bind phosphorylated receptors and cause receptor desensitization. Arrestins activated by interaction with phosphorylated receptors can also mediate G-protein-independent signalling by serving as adaptors to link receptors to numerous signalling pathways. Despite their central role in regulation and signalling of GPCRs, a structural understanding of β-arrestin activation and interaction with GPCRs is still lacking. Here we report the crystal structure of β-arrestin-1 (also called arrestin-2) in complex with a fully phosphorylated 29-amino-acid carboxy-terminal peptide derived from the human V2 vasopressin receptor (V2Rpp). This peptide has previously been shown to functionally and conformationally activate β-arrestin-1 (ref. 5). To capture this active conformation, we used a conformationally selective synthetic antibody fragment (Fab30) that recognizes the phosphopeptide-activated state of β-arrestin-1. The structure of the β-arrestin-1–V2Rpp–Fab30 complex shows marked conformational differences in β-arrestin-1 compared to its inactive conformation. These include rotation of the amino- and carboxy-terminal domains relative to each other, and a major reorientation of the ‘lariat loop’ implicated in maintaining the inactive state of β-arrestin-1. These results reveal, at high resolution, a receptor-interacting interface on β-arrestin, and they indicate a potentially general molecular mechanism for activation of these multifunctional signalling and regulatory proteins.

doi: 10.1038/nature12120

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構造生物学:活性化前状態にあるアレスチンp44の結晶構造

Crystal structure of pre-activated arrestin p44 p.142

Arrestins interact with G-protein-coupled receptors (GPCRs) to block interaction with G proteins and initiate G-protein-independent signalling. Arrestins have a bi-lobed structure that is stabilized by a long carboxy-terminal tail (C-tail), and displacement of the C-tail by receptor-attached phosphates activates arrestins for binding active GPCRs. Structures of the inactive state of arrestin are available, but it is not known how C-tail displacement activates arrestin for receptor coupling. Here we present a 3.0 Å crystal structure of the bovine arrestin-1 splice variant p44, in which the activation step is mimicked by C-tail truncation. The structure of this pre-activated arrestin is profoundly different from the basal state and gives insight into the activation mechanism. p44 displays breakage of the central polar core and other interlobe hydrogen-bond networks, leading to a ∼21° rotation of the two lobes as compared to basal arrestin-1. Rearrangements in key receptor-binding loops in the central crest region include the finger loop, loop 139 (refs 8, 10, 11) and the sequence Asp 296–Asn 305 (or gate loop), here identified as controlling the polar core. We verified the role of these conformational alterations in arrestin activation and receptor binding by site-directed fluorescence spectroscopy. The data indicate a mechanism for arrestin activation in which C-tail displacement releases critical central-crest loops from restricted to extended receptor-interacting conformations. In parallel, increased flexibility between the two lobes facilitates a proper fitting of arrestin to the active receptor surface. Our results provide a snapshot of an arrestin ready to bind the active receptor, and give an insight into the role of naturally occurring truncated arrestins in the visual system.

doi: 10.1038/nature12133

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