Editorials
脳を電気刺激して認知機能改善を図る装置は、自製も可能で利用が増えそうだが、効果は不明でリスクもあり、監視が必要だ。
Brain blast p.271
DIY attempts at electrical brain stimulation to improve cognition are to get easier.
doi: 10.1038/498271b
地球規模での地震の危険度算定を目指すグローバル地震モデル計画は、より良い危機管理に向けた第一歩である。
Risk management p.271
A project to pool data and tools to calculate earthquake hazards is an important milestone, but it will be down to individuals to decide how to interpret and respond to those risks.
doi: 10.1038/498271a
米オバマ政権は事後避妊薬の年齢制限を断念したが、これは科学機関に政治を持ち込むべきでないという教訓だ。
Science prevails p.272
The US government gives up its fight to keep age restrictions on the morning-after pill.
doi: 10.1038/498272a
News
NASAが、探査機アイリスで、太陽の表面とコロナの境界面を観測へ。
NASA sets sights on the Sun p.279
IRIS mission aims to scrutinize the layer between the star’s surface and its flickering corona.
doi: 10.1038/498279a
クォーク4個からなる粒子が確認され、新たな「物質」の世界が。
Quark quartet opens fresh vista on matter p.280
First particle containing four quarks is confirmed.
doi: 10.1038/498280a
米最高裁が天然のヒト遺伝子の特許は認めないと判決を下し、バイオ業界に混乱が。
Myriad ruling causes confusion p.281
Change to gene patents leaves US biotech in a lather.
doi: 10.1038/498281a
イヌの家畜化過程をめぐって、遺伝学者たちが激しい論争を。
Dog genetics spur scientific spat p.282
Researchers disagree over canine domestication.
doi: 10.1038/498282a
グラクソ・スミスクライン社が、誤りのある論文撤回を拒否した中国の研究部門のトップを解雇。
China drugs head fired over article row p.283
Researcher stands by results despite demand for retraction.
doi: 10.1038/498283a
旧ソ連の月面探査機は、実はNASAの火星探査機よりも探査距離が長かったことが明らかに。
Space rovers in record race p.284
Revised data show Soviet Union’s 1970s lunar vehicle outdistanced NASA’s Opportunity — for now.
doi: 10.1038/498284a
News Features
コンピューター：量子企業
Computing: The quantum company p.286
D-Wave社は量子コンピューター作製の新しい方式を開発したパイオニアだが、論争も招いている。
doi: 10.1038/498286a
地震学：地震を捉える
Seismology: Quake catcher p.290
増え続ける地震被害を軽減しようと、Ross Steinは、世界の地震リスク地図作成を目指している。
doi: 10.1038/498290a
News & Views
フォーラム：大気科学：雲の中の氷の種
Atmospheric science: The seeds of ice in clouds p.302
雲の中で起こる液滴凍結過程についての研究から、大気中の鉱物ダストに含まれる微量成分の1つがこの過程の主要な触媒として働いていることが示唆された。この知見が雲での液滴凍結の研究や大気エアロゾル研究に及ぼす複雑な影響について、2人の専門家が論じている。
doi: 10.1038/nature12256
行動生物学：考古学の観点から霊長類の技術を見る
Behavioural biology: Archaeology meets primate technology p.303
石をハンマーとして使って木の実を割る野生のオマキザルについての研究から、このサルが道具として使っていた石などの時間・空間的変化パターンが明らかになり、このような挙動が考古学的視点から検討可能であることが確証された。
doi: 10.1038/498303a
HIV：組み込みが死を招く
HIV: Integration triggers death p.305
HIVがCD4+ T細胞を殺して免疫系を働けなくすることはずっと以前から知られている。ウイルスが宿主細胞のゲノムに組み込まれることによって活性化されるタンパク質のDNA-PKが、細胞死を引き起こす「工作員」であることが今回明らかになった。
doi: 10.1038/nature12254
バイオミメティクス：ハエそっくりに飛ぶ
Biomimetics: Flying like a fly p.306
昆虫の飛翔の原理が生物学によって明らかにされたことが、技術者が航空力学で功績を挙げるためのヒントとなった。微細加工技術の進歩によって、今回初めてロボットハエが飛行できるようになった。
doi: 10.1038/nature12258
物理学：重いカルシウム原子核を計量する
Physics: Heavy calcium nuclei weigh in p.307
カルシウム原子核は、その構造のために原子核の性質を研究する際の良いテストケースとなる。2種類の重いカルシウム原子核の質量が計測され、原子核モデルのための基準が得られた。
doi: 10.1038/498307a
構造生物学：構造に秩序のないタンパク質でのシグナル伝達
Structural biology: Signalling from disordered proteins p.308
無秩序な構造を持つタンパク質でも、機能の異なる2つの結合部位の間でシグナル伝達ができることがわかり、タンパク質内の情報伝達には、こうした部位をつなぐ特定の構造経路が必要であるという考えに疑問が投げかけられることになった。
doi: 10.1038/498308a
ウイルス学：親族がぞくぞくと増えているウイルス
Virology: The virus whose family expanded p.310
遺伝的多様性に極めて富んだヘパシウイルス属およびpegivirus属に分類される新種ウイルスが、野生の齧歯類やコウモリ個体群で多数見つかったことは、C型肝炎ウイルスの起源を明らかにするのに役立ちそうだ。
doi: 10.1038/498310b
Articles
工学：ホログラフィックビデオディスプレイに使う異方的な漏洩モード変調器
Anisotropic leaky-mode modulator for holographic video displays p.313
Realizing holographic video displays is proving far from straightforward, but it is shown here that it may be possible to overcome the limitations of present displays by harnessing the desirable optical manipulation properties of anisotropic leaky-mode spatial light modulators.
doi: 10.1038/nature12217
発生生物学：直鎖状ユビキチン特異的な脱ユビキチン化酵素gumbyは血管形成を制御する
The linear ubiquitin-specific deubiquitinase gumby regulates angiogenesis p.318
This study identifies a deubiquitinase (DUB) that specifically recognises and cleaves linear ubiquitin chains, implicating linear (de)ubiquitination in Wnt signalling and angiogenesis; mutations in gumby cause defects in angiogenesis in mice, and structural and biochemical analysis shows that gumby encodes a linear-ubiquitin-specific DUB.
doi: 10.1038/nature12296
神経科学：RAS–MAPK–MSK1経路はSCA1でアタキシン1タンパク質の量と毒性を調節する
RAS–MAPK–MSK1 pathway modulates ataxin 1 protein levels and toxicity in SCA1 p.325
Cross-species genetic screens reveal that decreased mitogen-activated protein kinase signalling reduces polyglutamine-expanded ataxin 1 levels and toxicity in models of spinocerebellar ataxia type 1.
doi: 10.1038/nature12204
構造生物学：cGASによる細胞質内DNA感知の構造的機序
Structural mechanism of cytosolic DNA sensing by cGAS p.332
Cytosolic DNA arising from intracellular bacterial or viral infections induces type I interferon through activation of the DNA sensor cGAS, which catalyses the synthesis of cyclic dinucleotide which in turn activates STING; here the crystal structures of a carboxy-terminal fragment of cGAS alone and in complex with UTP and DNA–ATP–GTP complex are determined.
doi: 10.1038/nature12305
Letters
宇宙物理学：赤方偏移2.3の位置にある太陽の4000億倍の質量を持った楕円銀河の急速な形成
The rapid assembly of an elliptical galaxy of 400 billion solar masses at a redshift of 2.3 p.338
Stellar archaeology shows that massive elliptical galaxies formed rapidly about ten billion years ago with star-formation rates of above several hundred solar masses per year. Their progenitors are probably the submillimetre bright galaxies at redshifts z greater than 2. Although the mean molecular gas mass (5 × 1010 solar masses) of the submillimetre bright galaxies can explain the formation of typical elliptical galaxies, it is inadequate to form elliptical galaxies that already have stellar masses above 2 × 1011 solar masses at z ≈ 2. Here we report multi-wavelength high-resolution observations of a rare merger of two massive submillimetre bright galaxies at z = 2.3. The system is seen to be forming stars at a rate of 2,000 solar masses per year. The star-formation efficiency is an order of magnitude greater than that of normal galaxies, so the gas reservoir will be exhausted and star formation will be quenched in only around 200 million years. At a projected separation of 19 kiloparsecs, the two massive starbursts are about to merge and form a passive elliptical galaxy with a stellar mass of about 4 × 1011 solar masses. We conclude that gas-rich major galaxy mergers with intense star formation can form the most massive elliptical galaxies by z ≈ 1.5.
doi: 10.1038/nature12184
惑星科学：上部マントルの初期酸化作用によって制御された火星の火山活動
Volcanism on Mars controlled by early oxidation of the upper mantle p.342
Detailed information about the chemical composition and evolution of Mars has been derived principally from the SNC (shergottite–nakhlite–chassignite) meteorites, which are genetically related igneous rocks of Martian origin. They are chemically and texturally similar to terrestrial basalts and cumulates, except that they have higher concentrations of iron and volatile elements such as phosphorus and chlorine and lower concentrations of nickel and other chalcophile (sulphur-loving) elements. Most Martian meteorites have relatively young crystallization ages (1.4 billion years to 180 million years ago) and are considered to be derived from young, lightly cratered volcanic regions, such as the Tharsis plateau. Surface rocks from the Gusev crater analysed by the Spirit rover are much older (about 3.7 billion years old) and exhibit marked compositional differences from the meteorites. Although also basaltic in composition, the surface rocks are richer in nickel and sulphur and have lower manganese/iron ratios than the meteorites. This has led to doubts that Mars can be described adequately using the ‘SNC model’. Here we show, however, that the differences between the compositions of meteorites and surface rocks can be explained by differences in the oxygen fugacity during melting of the same sulphur-rich mantle. This ties the sources of Martian meteorites to those of the surface rocks through an early (>3.7 billion years ago) oxidation of the uppermost mantle that had less influence on the deeper regions, which produce the more recent volcanic rocks.
doi: 10.1038/nature12225
核物理：カルシウムのエキゾチック同位体の質量によって核力が明確になる
Masses of exotic calcium isotopes pin down nuclear forces p.346
The properties of exotic nuclei on the verge of existence play a fundamental part in our understanding of nuclear interactions. Exceedingly neutron-rich nuclei become sensitive to new aspects of nuclear forces. Calcium, with its doubly magic isotopes 40Ca and 48Ca, is an ideal test for nuclear shell evolution, from the valley of stability to the limits of existence. With a closed proton shell, the calcium isotopes mark the frontier for calculations with three-nucleon forces from chiral effective field theory. Whereas predictions for the masses of 51Ca and 52Ca have been validated by direct measurements, it is an open question as to how nuclear masses evolve for heavier calcium isotopes. Here we report the mass determination of the exotic calcium isotopes 53Ca and 54Ca, using the multi-reflection time-of-flight mass spectrometer of ISOLTRAP at CERN. The measured masses unambiguously establish a prominent shell closure at neutron number N = 32, in excellent agreement with our theoretical calculations. These results increase our understanding of neutron-rich matter and pin down the subtle components of nuclear forces that are at the forefront of theoretical developments constrained by quantum chromodynamics.
doi: 10.1038/nature12226
化学：氷の均一融解における制御段階としての欠陥対分離
Defect pair separation as the controlling step in homogeneous ice melting p.350
On being heated, ice melts into liquid water. Although in practice this process tends to be heterogeneous, it can occur homogeneously inside bulk ice. The thermally induced homogeneous melting of solids is fairly well understood, and involves the formation and growth of melting nuclei. But in the case of water, resilient hydrogen bonds render ice melting more complex. We know that the first defects appearing during homogeneous ice melting are pairs of five- and seven-membered rings, which appear and disappear repeatedly and randomly in space and time in the crystalline ice structure. However, the accumulation of these defects to form an aggregate is nearly additive in energy, and results in a steep free energy increase that suppresses further growth. Here we report molecular dynamics simulations of homogeneous ice melting that identify as a crucial first step not the formation but rather the spatial separation of a defect pair. We find that once it is separated, the defect pair—either an interstitial (I) and a vacancy (V) defect pair (a Frenkel pair), or an L and a D defect pair (a Bjerrum pair)—is entropically stabilized, or ‘entangled’. In this state, defects with threefold hydrogen-bond coordination persist and grow, and thereby prepare the system for subsequent rapid melting.
doi: 10.1038/nature12190
気候：混合相雲での鉱物ダストによる氷の核形成における長石の重要性
The importance of feldspar for ice nucleation by mineral dust in mixed-phase clouds p.355
The amount of ice present in mixed-phase clouds, which contain both supercooled liquid water droplets and ice particles, affects cloud extent, lifetime, particle size and radiative properties. The freezing of cloud droplets can be catalysed by the presence of aerosol particles known as ice nuclei. One of the most important ice nuclei is thought to be mineral dust aerosol from arid regions. It is generally assumed that clay minerals, which contribute approximately two-thirds of the dust mass, dominate ice nucleation by mineral dust, and many experimental studies have therefore focused on these materials. Here we use an established droplet-freezing technique to show that feldspar minerals dominate ice nucleation by mineral dusts under mixed-phase cloud conditions, despite feldspar being a minor component of dust emitted from arid regions. We also find that clay minerals are relatively unimportant ice nuclei. Our results from a global aerosol model study suggest that feldspar ice nuclei are globally distributed and that feldspar particles may account for a large proportion of the ice nuclei in Earth’s atmosphere that contribute to freezing at temperatures below about −15 °C.
doi: 10.1038/nature12278
古生物学：中国で出土したジュラ紀の鳥群恐竜化石によって明らかになった鳥類の初期系統発生史
A Jurassic avialan dinosaur from China resolves the early phylogenetic history of birds p.359
The recent discovery of small paravian theropod dinosaurs with well-preserved feathers in the Middle–Late Jurassic Tiaojishan Formation of Liaoning Province (northeastern China) has challenged the pivotal position of Archaeopteryx, regarded from its discovery to be the most basal bird. Removing Archaeopteryx from the base of Avialae to nest within Deinonychosauria implies that typical bird flight, powered by the forelimbs only, either evolved at least twice, or was subsequently lost or modified in some deinonychosaurians. Here we describe the complete skeleton of a new paravian from the Tiaojishan Formation of Liaoning Province, China. Including this new taxon in a comprehensive phylogenetic analysis for basal Paraves does the following: (1) it recovers it as the basal-most avialan; (2) it confirms the avialan status of Archaeopteryx; (3) it places Troodontidae as the sister-group to Avialae; (4) it supports a single origin of powered flight within Paraves; and (5) it implies that the early diversification of Paraves and Avialae took place in the Middle–Late Jurassic period.
doi: 10.1038/nature12168
神経科学：前前頭皮質の2つのタイプの介在ニューロン群は別個の行動相関とネットワーク相関を示す
Distinct behavioural and network correlates of two interneuron types in prefrontal cortex p.363
Neurons in the prefrontal cortex exhibit diverse behavioural correlates, an observation that has been attributed to cell-type diversity. To link identified neuron types with network and behavioural functions, we recorded from the two largest genetically defined inhibitory interneuron classes, the perisomatically targeting parvalbumin (PV) and the dendritically targeting somatostatin (SOM) neurons in anterior cingulate cortex of mice performing a reward foraging task. Here we show that PV and a subtype of SOM neurons form functionally homogeneous populations showing a double dissociation between both their inhibitory effects and behavioural correlates. Out of several events pertaining to behaviour, a subtype of SOM neurons selectively responded at reward approach, whereas PV neurons responded at reward leaving and encoded preceding stay duration. These behavioural correlates of PV and SOM neurons defined a behavioural epoch and a decision variable important for foraging (whether to stay or to leave), a crucial function attributed to the anterior cingulate cortex. Furthermore, PV neurons could fire in millisecond synchrony, exerting fast and powerful inhibition on principal cell firing, whereas the inhibitory effect of SOM neurons on firing output was weak and more variable, consistent with the idea that they respectively control the outputs of, and inputs to, principal neurons. These results suggest a connection between the circuit-level function of different interneuron types in regulating the flow of information and the behavioural functions served by the cortical circuits. Moreover, these observations bolster the hope that functional response diversity during behaviour can in part be explained by cell-type diversity.
doi: 10.1038/nature12176
医学：ヒト皮膚における真菌群集および細菌群集の部位による多様性
Topographic diversity of fungal and bacterial communities in human skin p.367
Traditional culture-based methods have incompletely defined the microbial landscape of common recalcitrant human fungal skin diseases, including athlete’s foot and toenail infections. Skin protects humans from invasion by pathogenic microorganisms and provides a home for diverse commensal microbiota. Bacterial genomic sequence data have generated novel hypotheses about species and community structures underlying human disorders. However, microbial diversity is not limited to bacteria; microorganisms such as fungi also have major roles in microbial community stability, human health and disease. Genomic methodologies to identify fungal species and communities have been limited compared with those that are available for bacteria. Fungal evolution can be reconstructed with phylogenetic markers, including ribosomal RNA gene regions and other highly conserved genes. Here we sequenced and analysed fungal communities of 14 skin sites in 10 healthy adults. Eleven core-body and arm sites were dominated by fungi of the genus Malassezia, with only species-level classifications revealing fungal-community composition differences between sites. By contrast, three foot sites—plantar heel, toenail and toe web—showed high fungal diversity. Concurrent analysis of bacterial and fungal communities demonstrated that physiologic attributes and topography of skin differentially shape these two microbial communities. These results provide a framework for future investigation of the contribution of interactions between pathogenic and commensal fungal and bacterial communities to the maintainenace of human health and to disease pathogenesis.
doi: 10.1038/nature12171
細胞：好中球の遊走群はin vivoの細胞死部位でLTB4およびインテグリンを必要とする
Neutrophil swarms require LTB4 and integrins at sites of cell death in vivo p.371
Neutrophil recruitment from blood to extravascular sites of sterile or infectious tissue damage is a hallmark of early innate immune responses, and the molecular events leading to cell exit from the bloodstream have been well defined. Once outside the vessel, individual neutrophils often show extremely coordinated chemotaxis and cluster formation reminiscent of the swarming behaviour of insects. The molecular players that direct this response at the single-cell and population levels within the complexity of an inflamed tissue are unknown. Using two-photon intravital microscopy in mouse models of sterile injury and infection, we show a critical role for intercellular signal relay among neutrophils mediated by the lipid leukotriene B4, which acutely amplifies local cell death signals to enhance the radius of highly directed interstitial neutrophil recruitment. Integrin receptors are dispensable for long-distance migration, but have a previously unappreciated role in maintaining dense cellular clusters when congregating neutrophils rearrange the collagenous fibre network of the dermis to form a collagen-free zone at the wound centre. In this newly formed environment, integrins, in concert with neutrophil-derived leukotriene B4 and other chemoattractants, promote local neutrophil interaction while forming a tight wound seal. This wound seal has borders that cease to grow in kinetic concert with late recruitment of monocytes and macrophages at the edge of the displaced collagen fibres. Together, these data provide an initial molecular map of the factors that contribute to neutrophil swarming in the extravascular space of a damaged tissue. They reveal how local events are propagated over large-range distances, and how auto-signalling produces coordinated, self-organized neutrophil-swarming behaviour that isolates the wound or infectious site from surrounding viable tissue.
doi: 10.1038/nature12175
医学：HIV-1はウイルス組み込みの間にDNA依存性プロテインキナーゼを介してCD4細胞死を引き起こす
HIV-1 causes CD4 cell death through DNA-dependent protein kinase during viral integration p.376
Human immunodeficiency virus-1 (HIV-1) has infected more than 60 million people and caused nearly 30 million deaths worldwide, ultimately the consequence of cytolytic infection of CD4+ T cells. In humans and in macaque models, most of these cells contain viral DNA and are rapidly eliminated at the peak of viraemia, yet the mechanism by which HIV-1 induces helper T-cell death has not been defined. Here we show that virus-induced cell killing is triggered by viral integration. Infection by wild-type HIV-1, but not an integrase-deficient mutant, induced the death of activated primary CD4 lymphocytes. Similarly, raltegravir, a pharmacologic integrase inhibitor, abolished HIV-1-induced cell killing both in cell culture and in CD4+ T cells from acutely infected subjects. The mechanism of killing during viral integration involved the activation of DNA-dependent protein kinase (DNA-PK), a central integrator of the DNA damage response, which caused phosphorylation of p53 and histone H2AX. Pharmacological inhibition of DNA-PK abolished cell death during HIV-1 infection in vitro, suggesting that processes which reduce DNA-PK activation in CD4 cells could facilitate the formation of latently infected cells that give rise to reservoirs in vivo. We propose that activation of DNA-PK during viral integration has a central role in CD4+ T-cell depletion, raising the possibility that integrase inhibitors and interventions directed towards DNA-PK may improve T-cell survival and immune function in infected individuals.
doi: 10.1038/nature12274
免疫：cGASはSTINGを活性化するセカンドメッセンジャーの2′-5′結合環状ジヌクレオチドを産生する
cGAS produces a 2′-5′-linked cyclic dinucleotide second messenger that activates STING p.380
Detection of cytoplasmic DNA represents one of the most fundamental mechanisms of the innate immune system to sense the presence of microbial pathogens. Moreover, erroneous detection of endogenous DNA by the same sensing mechanisms has an important pathophysiological role in certain sterile inflammatory conditions. The endoplasmic-reticulum-resident protein STING is critically required for the initiation of type I interferon signalling upon detection of cytosolic DNA of both exogenous and endogenous origin. Next to its pivotal role in DNA sensing, STING also serves as a direct receptor for the detection of cyclic dinucleotides, which function as second messenger molecules in bacteria. DNA recognition, however, is triggered in an indirect fashion that depends on a recently characterized cytoplasmic nucleotidyl transferase, termed cGAMP synthase (cGAS), which upon interaction with DNA synthesizes a dinucleotide molecule that in turn binds to and activates STING. We here show in vivo and in vitro that the cGAS-catalysed reaction product is distinct from previously characterized cyclic dinucleotides. Using a combinatorial approach based on mass spectrometry, enzymatic digestion, NMR analysis and chemical synthesis we demonstrate that cGAS produces a cyclic GMP-AMP dinucleotide, which comprises a 2′-5′ and a 3′-5′ phosphodiester linkage >Gp(2′-5′)Ap(3′-5′)>. We found that the presence of this 2′-5′ linkage was required to exert potent activation of human STING. Moreover, we show that cGAS first catalyses the synthesis of a linear 2′-5′-linked dinucleotide, which is then subject to cGAS-dependent cyclization in a second step through a 3′-5′ phosphodiester linkage. This 13-membered ring structure defines a novel class of second messenger molecules, extending the family of 2′-5′-linked antiviral biomolecules.
doi: 10.1038/nature12306
細胞：ポリメラーゼIVがRNA指令型DNAメチル化部位に結合するにはSHH1が必要である
Polymerase IV occupancy at RNA-directed DNA methylation sites requires SHH1 p.385
DNA methylation is an epigenetic modification that has critical roles in gene silencing, development and genome integrity. In Arabidopsis, DNA methylation is established by DOMAINS REARRANGED METHYLTRANSFERASE 2 (DRM2) and targeted by 24-nucleotide small interfering RNAs (siRNAs) through a pathway termed RNA-directed DNA methylation (RdDM). This pathway requires two plant-specific RNA polymerases: Pol-IV, which functions to initiate siRNA biogenesis, and Pol-V, which functions to generate scaffold transcripts that recruit downstream RdDM factors. To understand the mechanisms controlling Pol-IV targeting we investigated the function of SAWADEE HOMEODOMAIN HOMOLOG 1 (SHH1), a Pol-IV-interacting protein. Here we show that SHH1 acts upstream in the RdDM pathway to enable siRNA production from a large subset of the most active RdDM targets, and that SHH1 is required for Pol-IV occupancy at these same loci. We also show that the SHH1 SAWADEE domain is a novel chromatin-binding module that adopts a unique tandem Tudor-like fold and functions as a dual lysine reader, probing for both unmethylated K4 and methylated K9 modifications on the histone 3 (H3) tail. Finally, we show that key residues within both lysine-binding pockets of SHH1 are required in vivo to maintain siRNA and DNA methylation levels as well as Pol-IV occupancy at RdDM targets, demonstrating a central role for methylated H3K9 binding in SHH1 function and providing the first insights into the mechanism of Pol-IV targeting. Given the parallels between methylation systems in plants and mammals, a further understanding of this early targeting step may aid our ability to control the expression of endogenous and newly introduced genes, which has broad implications for agriculture and gene therapy.
doi: 10.1038/nature12178
生物物理：タンパク質の本質的な無秩序性によるアロステリック性の調節
Modulation of allostery by protein intrinsic disorder p.390
Allostery is an intrinsic property of many globular proteins and enzymes that is indispensable for cellular regulatory and feedback mechanisms. Recent theoretical and empirical observations indicate that allostery is also manifest in intrinsically disordered proteins, which account for a substantial proportion of the proteome. Many intrinsically disordered proteins are promiscuous binders that interact with multiple partners and frequently function as molecular hubs in protein interaction networks. The adenovirus early region 1A (E1A) oncoprotein is a prime example of a molecular hub intrinsically disordered protein. E1A can induce marked epigenetic reprogramming of the cell within hours after infection, through interactions with a diverse set of partners that include key host regulators such as the general transcriptional coactivator CREB binding protein (CBP), its paralogue p300, and the retinoblastoma protein (pRb; also called RB1). Little is known about the allosteric effects at play in E1A–CBP–pRb interactions, or more generally in hub intrinsically disordered protein interaction networks. Here we used single-molecule fluorescence resonance energy transfer (smFRET) to study coupled binding and folding processes in the ternary E1A system. The low concentrations used in these high-sensitivity experiments proved to be essential for these studies, which are challenging owing to a combination of E1A aggregation propensity and high-affinity binding interactions. Our data revealed that E1A–CBP–pRb interactions have either positive or negative cooperativity, depending on the available E1A interaction sites. This striking cooperativity switch enables fine-tuning of the thermodynamic accessibility of the ternary versus binary E1A complexes, and may permit a context-specific tuning of associated downstream signalling outputs. Such a modulation of allosteric interactions is probably a common mechanism in molecular hub intrinsically disordered protein function.
doi: 10.1038/nature12294
