네이처 컨텐츠

Editorials

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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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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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

News Features

Tarnished promise p.21

Genetically modified crops generate hype and hatred. A special section of Nature cuts through the drama.

doi: 10.1038/497021a

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A hard look at GM crops p.24

Superweeds? Suicides? Stealthy genes? The true, the false and the still unknown about transgenic crops.

Natasha Gilbert

doi: 10.1038/497024a

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A new breed p.27

The next wave of genetically modified crops is making its way to market — and might just ease concerns over 'Frankenfoods'.

Daniel Cressey

doi: 10.1038/497027a

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News & Views

Navigation with a cognitive map p.42

Hippocampal place cells encode information about an animal's spatial world. A study now finds that these same neurons envisage a future journey moments before a rat sets off. See Article p.74

Brandy Schmidt & A. David Redish

doi: 10.1038/nature12095

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Small differences in sameness p.43

Fresh evidence shows that the iron isotopic composition of Earth's silicate component does not, as was previously thought, reflect the formation of the planet's core at high pressure nor losses of material to space.

Alex N. Halliday

doi: 10.1038/497043a

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Active arrestin proteins crystallized p.45

Arrestin proteins regulate cellular signalling cascades initiated by ubiquitous G-protein-coupled receptors. Crystal structures reveal that two arrestins undergo similar structural changes on activation. See Letters p.137 & p.142

Valentin Borshchevskiy & Georg Büldt

doi: 10.1038/nature12096

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Single spins in silicon see the light p.46

The spin state of a single erbium atom in a tiny silicon transistor has been probed using laser light. The finding opens a path towards a hybrid spin–photon quantum-computing architecture. See Letter p.91

Christoph D. Weis & Thomas Schenkel

doi: 10.1038/497046a

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

An elegant combination of electronics and elastic materials has been used to construct a small visual sensor that closely resembles an insect's eye. The device paves the way for autonomous navigation of tiny aerial vehicles. See Letter p.95

Alexander Borst & Johannes Plett

doi: 10.1038/497047a

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The ends justify the means p.48

A genomic analysis of yeast reveals that individual genes produce a rich complexity of RNA molecules with differing start and end sequences. The variation in these transcripts reflects the diversity of gene-regulation mechanisms. See Letter p.127

B. Franklin Pugh

doi: 10.1038/nature12098

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Oxidation controls the DUB step p.49

Reversible oxidation of amino-acid residues can directly regulate the activity of cellular enzymes. This principle has now been extended to deubiquitinating enzymes, with implications for cell signalling and protein turnover.

Michael J. Clague

doi: 10.1038/497049a

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Perspectives

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.

Dirk Helbing

doi: 10.1038/nature12047

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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.

Julian I. Schroeder, Emmanuel Delhaize, Wolf B. Frommer, Mary Lou Guerinot, Maria J. Harrison, Luis Herrera-Estrella, Tomoaki Horie, Leon V. Kochian, Rana Munns, Naoko K. Nishizawa + et al.

doi: 10.1038/nature11909

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Articles

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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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.

Brad E. Pfeiffer & David J. Foster

doi: 10.1038/nature12112

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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.

Andreas M. Anger, Jean-Paul Armache, Otto Berninghausen, Michael Habeck, Marion Subklewe, Daniel N. Wilson & Roland Beckmann

doi: 10.1038/nature12104

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Letters

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.

H. Bernien, B. Hensen, W. Pfaff, G. Koolstra, M. S. Blok, L. Robledo, T. H. Taminiau, M. Markham, D. J. Twitchen, L. Childress + et al.

doi: 10.1038/nature12016

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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.

Chunming Yin, Milos Rancic, Gabriele G. de Boo, Nikolas Stavrias, Jeffrey C. McCallum, Matthew J. Sellars & Sven Rogge

doi: 10.1038/nature12081

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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).

Young Min Song, Yizhu Xie, Viktor Malyarchuk, Jianliang Xiao, Inhwa Jung, Ki-Joong Choi, Zhuangjian Liu, Hyunsung Park, Chaofeng Lu, Rak-Hwan Kim + et al.

doi: 10.1038/nature12083

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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.

Christopher T. Reinhard, Noah J. Planavsky & Timothy W. Lyons

doi: 10.1038/nature12021

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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.

Vivian Allen, Karl T. Bates, Zhiheng Li & John R. Hutchinson

doi: 10.1038/nature12059

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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.

Muhammed Murtaza, Sarah-Jane Dawson, Dana W. Y. Tsui, Davina Gale, Tim Forshew, Anna M. Piskorz, Christine Parkinson, Suet-Feung Chin, Zoya Kingsbury, Alvin S. C. Wong + et al.

doi: 10.1038/nature12065

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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.

Sophie J. C. Caron, Vanessa Ruta, L. F. Abbott & Richard Axel

doi: 10.1038/nature12063

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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.

Christopher S. Campbell & Arshad Desai

doi: 10.1038/nature12057

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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.

Myunggon Ko, Jungeun An, Hozefa S. Bandukwala, Lukas Chavez, Tarmo Äijö, William A. Pastor, Matthew F. Segal, Huiming Li, Kian Peng Koh, Harri Lähdesmäki + et al.

doi: 10.1038/nature12052

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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.

Vicent Pelechano, Wu Wei & Lars M. Steinmetz

doi: 10.1038/nature12121

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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.

Siddhesh S. Kamat, Howard J. Williams, Lawrence J. Dangott, Mrinmoy Chakrabarti & Frank M. Raushel

doi: 10.1038/nature12061

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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.

Arun K. Shukla, Aashish Manglik, Andrew C. Kruse, Kunhong Xiao, Rosana I. Reis, Wei-Chou Tseng, Dean P. Staus, Daniel Hilger, Serdar Uysal, Li-Yin Huang + et al.

doi: 10.1038/nature12120

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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.

Yong Ju Kim, Klaus Peter Hofmann, Oliver P. Ernst, Patrick Scheerer, Hui-Woog Choe & Martha E. Sommer

doi: 10.1038/nature12133

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