Editorials
IPCCは、時間をかけて有益で立派な報告書をまとめてきたが、今後は方針を変更し、焦点を絞って、より迅速な研究、評価を目指すべきだ。
The final assessment p.281
The Intergovernmental Panel on Climate Change has provided invaluable evidence for policy-makers, but giant reports should give way to nimbler, more relevant research.
doi: 10.1038/501281a
作家Thomas Pynchonは、科学と芸術の互いに実りある融合が実現できることを示した。
Book smart p.282
Novelist Thomas Pynchon shows that science and art can combine, with mutual benefit.
doi: 10.1038/501282b
暗号分野の専門家と立法府は、インターネットの安全性に対する信頼を取り戻すため、対策に取り組む必要がある。
Spooked p.282
Researchers and lawmakers must work to rebuild trust in secure Internet standards.
doi: 10.1038/501282a
News
ドイツの科学はメルケル首相の下で大きく伸びたが、次の選挙後には科学予算削減の恐れも。
Germany hits science high p.289
But election prompts fears that budgetary pressures may sap strong investment.
doi: 10.1038/501289a
コロンビアの研究者たちが、農地からの温室効果ガス放出を削減できる牧草の育種に成功。
Grass gets greener p.291
Plant secretion curbs greenhouse-gas emissions from soil.
doi: 10.1038/501291a
ALMA望遠鏡での労働条件をめぐるストライキが、チリの他の天文台にも波及する可能性が。
ALMA strike stirs up Chilean labour unions p.292
Other observatories watch for sharpened worker demands.
doi: 10.1038/501292a
イスラエルが、EU助成の占領地への拠出を認めないホライズン2020の規則をめぐり、強硬な拒否の姿勢を。
Israel in deadlock on Horizon 2020 p.293
Conciliation sought in talks on EU research guidelines.
doi: 10.1038/501293a
データ不足が、MERS（中東呼吸器症候群）コロナウイルスの研究の妨げに。
Progress stalled on coronavirus p.294
Lack of in-depth studies hampers efforts to identify source.
doi: 10.1038/501294a
News Features
地球の展望
Global warming: Outlook for earth p.297
気候変動の不確定要素と対策の必要性との間で難しい舵取り役を果たしてきたIPCCの、これまでとこれからを考える。
doi: 10.1038/501297a
IPCCの25年
Climate assessments: 25 years of the IPCC p.298
地球の気候の監視役を果たしてきたIPCCの歴史を振り返る。
doi: 10.1038/501298a
上げ潮
Climate science: Rising tide p.300
海面がどのくらいの範囲で、どのくらい速く、どの程度上昇するかを予測しようと、研究者たちは苦労を重ねている。
doi: 10.1038/501300a
気候変動問題の議長
IPCC: The climate chairman p.303
何百人もの専門家の意見をまとめるのは簡単ではないが、Ottmar Edenhoferは、着実に、そして哲学を持って、この責務を果たしている。
doi: 10.1038/501303a
News & Views
気候科学：休止の原因
Climate science: The cause of the pause p.318
東太平洋赤道域で観測された海洋表面の水温を要因として取り込んで作られた全球気候モデルは、近年の地球温暖化の休止に対する説明を与えてくれる。
doi: 10.1038/501318a
発生神経科学：ヒト脳のミニチュア
Developmental neuroscience: Miniature human brains p.319
自己組織化する三次元組織を幹細胞を使って作り出せることが実証された。発生中のヒト脳を模倣するこの組織は、神経発生障害のモデルを作製するのに使用できる。
doi: 10.1038/nature12552
海洋学：深海の山岳波
Oceanography: Mountain waves in the deep ocean p.321
内部山岳波は、大洋の動態を作り出すのに関わっており、深海の混合に大きく寄与している可能性がある。これらは、こうした波を次世代気候モデルに取り込むことを真剣に考慮する根拠となる。
doi: 10.1038/501321a
寄生虫学：相手より一歩先んじる分子
Parasitology: Molecular one-upmanship p.322
病原体とその宿主は、果てしなく軍拡競争を続けている。病原性のトリパノソーマと、高密度リポタンパク質を含むヒト免疫複合体の1つも、そうした進化的にらみ合いを繰り広げている。
doi: 10.1038/501322a
材料科学：出世街道一目散の太陽電池
Materials science: Fast-track solar cells p.323
太陽電池産業が目指す究極の目標は、太陽光を高効率で電気に変換する廉価なデバイスである。ペロブスカイト半導体の登場は、この目標に到達するための重要なステップと考えられる。
doi: 10.1038/nature12557
幹細胞：ダウン症候群と老化のつながり
Stem cells: Down's syndrome link to ageing p.325
ダウン症候群のモデルでは酵素のUSP16の量が3倍になるが、これが成体組織に常在する幹細胞の欠陥を作り出すことが分かった。この知見は、加齢の際の幹細胞恒常性についての手がかりを与えてくれる。
doi: 10.1038/nature12558
Articles
発生：脳オルガノイドはヒトの脳発生と小頭症のモデルになる
Cerebral organoids model human brain development and microcephaly p.373
Here the authors present a human pluripotent stem cell-derived three-dimensional organoid culture system that is able to recapitulate several aspects of human brain development in addition to modelling the brain disorder microcephaly, which has been difficult to achieve using mouse models.
doi: 10.1038/nature12517
細胞：Usp16はダウン症候群に見られる体性幹細胞の異常に関与する
Usp16 contributes to somatic stem-cell defects in Down’s syndrome p.380
An analysis of somatic tissues derived from mouse models of Down’s syndrome shows reduced self-renewal capacities in various cell types, with these defects partially dependent on triplication of the Usp16 gene; overexpression and knockout studies in human cells shows that USP16 has a role in Down’s syndrome-related proliferation defects, making this gene an attractive option for further study.
doi: 10.1038/nature12530
構造生物学：βバレル膜タンパク質の生合成に関する構造的知見
Structural insight into the biogenesis of β-barrel membrane proteins p.385
The crystal structure of BamA, the central component of the β-barrel assembly machinery (BAM) complex, from N. gonorrhoeae and H. ducreyi is determined; the structure consists of an interior cavity capped by extracellular loops, an exterior rim with a narrowed hydrophobic surface and a lateral opening of the barrel domain, providing insight into a possible route for the insertion of β-barrel membrane proteins into the bacterial outer membrane.
doi: 10.1038/nature12521
Letters
宇宙：銀河系中心に位置する超大質量ブラックホール周辺の強力な磁場
A strong magnetic field around the supermassive black hole at the centre of the Galaxy p.391
Earth’s nearest candidate supermassive black hole lies at the centre of the Milky Way. Its electromagnetic emission is thought to be powered by radiatively inefficient accretion of gas from its environment, which is a standard mode of energy supply for most galactic nuclei. X-ray measurements have already resolved a tenuous hot gas component from which the black hole can be fed. The magnetization of the gas, however, which is a crucial parameter determining the structure of the accretion flow, remains unknown. Strong magnetic fields can influence the dynamics of accretion, remove angular momentum from the infalling gas, expel matter through relativistic jets and lead to synchrotron emission such as that previously observed. Here we report multi-frequency radio measurements of a newly discovered pulsar close to the Galactic Centre and show that the pulsar’s unusually large Faraday rotation (the rotation of the plane of polarization of the emission in the presence of an external magnetic field) indicates that there is a dynamically important magnetic field near the black hole. If this field is accreted down to the event horizon it provides enough magnetic flux to explain the observed emission—from radio to X-ray wavelengths—from the black hole.
doi: 10.1038/nature12499
工学：気相成長による効率の良いプレーナーヘテロ接合ペロブスカイト太陽電池
Efficient planar heterojunction perovskite solar cells by vapour deposition p.395
Many different photovoltaic technologies are being developed for large-scale solar energy conversion. The wafer-based first-generation photovoltaic devices have been followed by thin-film solid semiconductor absorber layers sandwiched between two charge-selective contacts and nanostructured (or mesostructured) solar cells that rely on a distributed heterojunction to generate charge and to transport positive and negative charges in spatially separated phases. Although many materials have been used in nanostructured devices, the goal of attaining high-efficiency thin-film solar cells in such a way has yet to be achieved. Organometal halide perovskites have recently emerged as a promising material for high-efficiency nanostructured devices. Here we show that nanostructuring is not necessary to achieve high efficiencies with this material: a simple planar heterojunction solar cell incorporating vapour-deposited perovskite as the absorbing layer can have solar-to-electrical power conversion efficiencies of over 15 per cent (as measured under simulated full sunlight). This demonstrates that perovskite absorbers can function at the highest efficiencies in simplified device architectures, without the need for complex nanostructures.
doi: 10.1038/nature12509
ナノ材料：非常に安定な銀ナノ粒子
Ultrastable silver nanoparticles p.399
Noble-metal nanoparticles have had a substantial impact across a diverse range of fields, including catalysis, sensing, photochemistry, optoelectronics, energy conversion and medicine. Although silver has very desirable physical properties, good relative abundance and low cost, gold nanoparticles have been widely favoured owing to their proved stability and ease of use. Unlike gold, silver is notorious for its susceptibility to oxidation (tarnishing), which has limited the development of important silver-based nanomaterials. Despite two decades of synthetic efforts, silver nanoparticles that are inert or have long-term stability remain unrealized. Here we report a simple synthetic protocol for producing ultrastable silver nanoparticles, yielding a single-sized molecular product in very large quantities with quantitative yield and without the need for size sorting. The stability, purity and yield are substantially better than those for other metal nanoparticles, including gold, owing to an effective stabilization mechanism. The particular size and stoichiometry of the product were found to be insensitive to variations in synthesis parameters. The chemical stability and structural, electronic and optical properties can be understood using first-principles electronic structure theory based on an experimental single-crystal X-ray structure. Although several structures have been determined for protected gold nanoclusters, none has been reported so far for silver nanoparticles. The total structure of a thiolate-protected silver nanocluster reported here uncovers the unique structure of the silver thiolate protecting layer, consisting of Ag2S5 capping structures. The outstanding stability of the nanoparticle is attributed to a closed-shell 18-electron configuration with a large energy gap between the highest occupied molecular orbital and the lowest unoccupied molecular orbital, an ultrastable 32-silver-atom excavated-dodecahedral core consisting of a hollow 12-silver-atom icosahedron encapsulated by a 20-silver-atom dodecahedron, and the choice of protective coordinating ligands. The straightforward synthesis of large quantities of pure molecular product promises to make this class of materials widely available for further research and technology development.
doi: 10.1038/nature12523
気候：太平洋赤道域表面の寒冷化と関連する近年の地球温暖化の休止
Recent global-warming hiatus tied to equatorial Pacific surface cooling p.403
Despite the continued increase in atmospheric greenhouse gas concentrations, the annual-mean global temperature has not risen in the twenty-first century, challenging the prevailing view that anthropogenic forcing causes climate warming. Various mechanisms have been proposed for this hiatus in global warming, but their relative importance has not been quantified, hampering observational estimates of climate sensitivity. Here we show that accounting for recent cooling in the eastern equatorial Pacific reconciles climate simulations and observations. We present a novel method of uncovering mechanisms for global temperature change by prescribing, in addition to radiative forcing, the observed history of sea surface temperature over the central to eastern tropical Pacific in a climate model. Although the surface temperature prescription is limited to only 8.2% of the global surface, our model reproduces the annual-mean global temperature remarkably well with correlation coefficient r = 0.97 for 1970–2012 (which includes the current hiatus and a period of accelerated global warming). Moreover, our simulation captures major seasonal and regional characteristics of the hiatus, including the intensified Walker circulation, the winter cooling in northwestern North America and the prolonged drought in the southern USA. Our results show that the current hiatus is part of natural climate variability, tied specifically to a La-Niña-like decadal cooling. Although similar decadal hiatus events may occur in the future, the multi-decadal warming trend is very likely to continue with greenhouse gas increase.
doi: 10.1038/nature12534
気候：トレーサー放出により測定されたドレーク海峡の中深度における等密度面を横切る急速な海洋混合
Rapid cross-density ocean mixing at mid-depths in the Drake Passage measured by tracer release p.408
Diapycnal mixing (across density surfaces) is an important process in the global ocean overturning circulation. Mixing in the interior of most of the ocean, however, is thought to have a magnitude just one-tenth of that required to close the global circulation by the downward mixing of less dense waters. Some of this deficit is made up by intense near-bottom mixing occurring in restricted ‘hot-spots’ associated with rough ocean-floor topography, but it is not clear whether the waters at mid-depth, 1,000 to 3,000 metres, are returned to the surface by cross-density mixing or by along-density flows. Here we show that diapycnal mixing of mid-depth (∼1,500 metres) waters undergoes a sustained 20-fold increase as the Antarctic Circumpolar Current flows through the Drake Passage, between the southern tip of South America and Antarctica. Our results are based on an open-ocean tracer release of trifluoromethyl sulphur pentafluoride. We ascribe the increased mixing to turbulence generated by the deep-reaching Antarctic Circumpolar Current as it flows over rough bottom topography in the Drake Passage. Scaled to the entire circumpolar current, the mixing we observe is compatible with there being a southern component to the global overturning in which about 20 sverdrups (1 Sv = 106 m3 s−1) upwell in the Southern Ocean, with cross-density mixing contributing a significant fraction (20 to 30 per cent) of this total, and the remainder upwelling along constant-density surfaces. The great majority of the diapycnal flux is the result of interaction with restricted regions of rough ocean-floor topography.
doi: 10.1038/nature12432
遺伝：生殖細胞系列のミトコンドリアDNAの変異は老化を促進し、脳発生を障害し得る
Germline mitochondrial DNA mutations aggravate ageing and can impair brain development p.412
Ageing is due to an accumulation of various types of damage, and mitochondrial dysfunction has long been considered to be important in this process. There is substantial sequence variation in mammalian mitochondrial DNA (mtDNA), and the high mutation rate is counteracted by different mechanisms that decrease maternal transmission of mutated mtDNA. Despite these protective mechanisms, it is becoming increasingly clear that low-level mtDNA heteroplasmy is quite common and often inherited in humans. We designed a series of mouse mutants to investigate the extent to which inherited mtDNA mutations can contribute to ageing. Here we report that maternally transmitted mtDNA mutations can induce mild ageing phenotypes in mice with a wild-type nuclear genome. Furthermore, maternally transmitted mtDNA mutations lead to anticipation of reduced fertility in mice that are heterozygous for the mtDNA mutator allele (PolgAwt/mut) and aggravate premature ageing phenotypes in mtDNA mutator mice (PolgAmut/mut). Unexpectedly, a combination of maternally transmitted and somatic mtDNA mutations also leads to stochastic brain malformations. Our findings show that a pre-existing mutation load will not only allow somatic mutagenesis to create a critically high total mtDNA mutation load sooner but will also increase clonal expansion of mtDNA mutations to enhance the normally occurring mosaic respiratory chain deficiency in ageing tissues. Our findings suggest that maternally transmitted mtDNA mutations may have a similar role in aggravating aspects of normal human ageing.
doi: 10.1038/nature12474
遺伝：生殖細胞におけるDNA損傷は全身的なストレス抵抗性の引き金となる自然免疫応答を誘導する
DNA damage in germ cells induces an innate immune response that triggers systemic stress resistance p.416
DNA damage responses have been well characterized with regard to their cell-autonomous checkpoint functions leading to cell cycle arrest, senescence and apoptosis. In contrast, systemic responses to tissue-specific genome instability remain poorly understood. In adult Caenorhabditis elegans worms germ cells undergo mitotic and meiotic cell divisions, whereas somatic tissues are entirely post-mitotic. Consequently, DNA damage checkpoints function specifically in the germ line, whereas somatic tissues in adult C. elegans are highly radio-resistant. Some DNA repair systems such as global-genome nucleotide excision repair (GG-NER) remove lesions specifically in germ cells. Here we investigated how genome instability in germ cells affects somatic tissues in C. elegans. We show that exogenous and endogenous DNA damage in germ cells evokes elevated resistance to heat and oxidative stress. The somatic stress resistance is mediated by the ERK MAP kinase MPK-1 in germ cells that triggers the induction of putative secreted peptides associated with innate immunity. The innate immune response leads to activation of the ubiquitin–proteasome system (UPS) in somatic tissues, which confers enhanced proteostasis and systemic stress resistance. We propose that elevated systemic stress resistance promotes endurance of somatic tissues to allow delay of progeny production when germ cells are genomically compromised.
doi: 10.1038/nature12452
がん：細胞老化において代謝を合成致死的に標的とするがん治療
Synthetic lethal metabolic targeting of cellular senescence in cancer therapy p.421
Activated oncogenes and anticancer chemotherapy induce cellular senescence, a terminal growth arrest of viable cells characterized by S-phase entry-blocking histone 3 lysine 9 trimethylation (H3K9me3). Although therapy-induced senescence (TIS) improves long-term outcomes, potentially harmful properties of senescent tumour cells make their quantitative elimination a therapeutic priority. Here we use the Eµ-myc transgenic mouse lymphoma model in which TIS depends on the H3K9 histone methyltransferase Suv39h1 to show the mechanism and therapeutic exploitation of senescence-related metabolic reprogramming in vitro and in vivo. After senescence-inducing chemotherapy, TIS-competent lymphomas but not TIS-incompetent Suv39h1– lymphomas show increased glucose utilization and much higher ATP production. We demonstrate that this is linked to massive proteotoxic stress, which is a consequence of the senescence-associated secretory phenotype (SASP) described previously. SASP-producing TIS cells exhibited endoplasmic reticulum stress, an unfolded protein response (UPR), and increased ubiquitination, thereby targeting toxic proteins for autophagy in an acutely energy-consuming fashion. Accordingly, TIS lymphomas, unlike senescence models that lack a strong SASP response, were more sensitive to blocking glucose utilization or autophagy, which led to their selective elimination through caspase-12- and caspase-3-mediated endoplasmic-reticulum-related apoptosis. Consequently, pharmacological targeting of these metabolic demands on TIS induction in vivo prompted tumour regression and improved treatment outcomes further. These findings unveil the hypercatabolic nature of TIS that is therapeutically exploitable by synthetic lethal metabolic targeting.
doi: 10.1038/nature12437
微生物学：細菌の定着因子は腸内微生物相の特異性および安定性を制御する
Bacterial colonization factors control specificity and stability of the gut microbiota p.426
Mammals harbour a complex gut microbiome, comprising bacteria that confer immunological, metabolic and neurological benefits. Despite advances in sequence-based microbial profiling and myriad studies defining microbiome composition during health and disease, little is known about the molecular processes used by symbiotic bacteria to stably colonize the gastrointestinal tract. We sought to define how mammals assemble and maintain the Bacteroides, one of the most numerically prominent genera of the human microbiome. Here we find that, whereas the gut normally contains hundreds of bacterial species, germ-free mice mono-associated with a single Bacteroides species are resistant to colonization by the same, but not different, species. To identify bacterial mechanisms for species-specific saturable colonization, we devised an in vivo genetic screen and discovered a unique class of polysaccharide utilization loci that is conserved among intestinal Bacteroides. We named this genetic locus the commensal colonization factors (ccf). Deletion of the ccf genes in the model symbiont, Bacteroides fragilis, results in colonization defects in mice and reduced horizontal transmission. The ccf genes of B. fragilis are upregulated during gut colonization, preferentially at the colonic surface. When we visualize microbial biogeography within the colon, B. fragilis penetrates the colonic mucus and resides deep within crypt channels, whereas ccf mutants are defective in crypt association. Notably, the CCF system is required for B. fragilis colonization following microbiome disruption with Citrobacter rodentium infection or antibiotic treatment, suggesting that the niche within colonic crypts represents a reservoir for bacteria to maintain long-term colonization. These findings reveal that intestinal Bacteroides have evolved species-specific physical interactions with the host that mediate stable and resilient gut colonization, and the CCF system represents a novel molecular mechanism for symbiosis.
doi: 10.1038/nature12447
医学：ガンビアトリパノソーマのヒト血清に対する抵抗性が生じる仕組み
Mechanism of Trypanosoma brucei gambiense resistance to human serum p.430
The African parasite Trypanosoma brucei gambiense accounts for 97% of human sleeping sickness cases. T. b. gambiense resists the specific human innate immunity acting against several other tsetse-fly-transmitted trypanosome species such as T. b. brucei, the causative agent of nagana disease in cattle. Human immunity to some African trypanosomes is due to two serum complexes designated trypanolytic factors (TLF-1 and -2), which both contain haptoglobin-related protein (HPR) and apolipoprotein LI (APOL1). Whereas HPR association with haemoglobin (Hb) allows TLF-1 binding and uptake via the trypanosome receptor TbHpHbR (ref. 5), TLF-2 enters trypanosomes independently of TbHpHbR (refs 4, 5). APOL1 kills trypanosomes after insertion into endosomal/lysosomal membranes. Here we report that T. b. gambiense resists TLFs via a hydrophobic β-sheet of the T. b. gambiense-specific glycoprotein (TgsGP), which prevents APOL1 toxicity and induces stiffening of membranes upon interaction with lipids. Two additional features contribute to resistance to TLFs: reduction of sensitivity to APOL1 requiring cysteine protease activity, and TbHpHbR inactivation due to a L210S substitution. According to such a multifactorial defence mechanism, transgenic expression of T. b. brucei TbHpHbR in T. b. gambiense did not cause parasite lysis in normal human serum. However, these transgenic parasites were killed in hypohaptoglobinaemic serum, after high TLF-1 uptake in the absence of haptoglobin (Hp) that competes for Hb and receptor binding. TbHpHbR inactivation preventing high APOL1 loading in hypohaptoglobinaemic serum may have evolved because of the overlapping endemic area of T. b. gambiense infection and malaria, the main cause of haemolysis-induced hypohaptoglobinaemia in western and central Africa.
doi: 10.1038/nature12516
免疫：ヤツメウナギにおける第三のリンパ球系列の進化との関わり
Evolutionary implications of a third lymphocyte lineage in lampreys p.435
Jawed vertebrates (gnathostomes) and jawless vertebrates (cyclostomes) have different adaptive immune systems. Gnathostomes use T- and B-cell antigen receptors belonging to the immunoglobulin superfamily. Cyclostomes, the lampreys and hagfish, instead use leucine-rich repeat proteins to construct variable lymphocyte receptors (VLRs), two types of which, VLRA and VLRB, are reciprocally expressed by lymphocytes resembling gnathostome T and B cells. Here we define another lineage of T-cell-like lymphocytes that express the recently identified VLRC receptors. Both VLRC+ and VLRA+ lymphocytes express orthologues of genes that gnathostome γδ and αβ T cells use for their differentiation, undergo VLRC and VLRA assembly and repertoire diversification in the ‘thymoid’ gill region, and express their VLRs solely as cell-surface proteins. Our findings suggest that the genetic programmes for two primordial T-cell lineages and a prototypic B-cell lineage were already present in the last common vertebrate ancestor approximately 500 million years ago. We propose that functional specialization of distinct T-cell-like lineages was an ancient feature of a primordial immune system.
doi: 10.1038/nature12467
免疫：ヒトモノクローナル抗体による4種類のパラミクソウイルスの交差中和
Cross-neutralization of four paramyxoviruses by a human monoclonal antibody p.439
Broadly neutralizing antibodies reactive against most and even all variants of the same viral species have been described for influenza and HIV-1 (ref. 1). However, whether a neutralizing antibody could have the breadth of range to target different viral species was unknown. Human respiratory syncytial virus (HRSV) and human metapneumovirus (HMPV) are common pathogens that cause severe disease in premature newborns, hospitalized children and immune-compromised patients, and play a role in asthma exacerbations. Although antisera generated against either HRSV or HMPV are not cross-neutralizing, we speculated that, because of the repeated exposure to these viruses, cross-neutralizing antibodies may be selected in some individuals. Here we describe a human monoclonal antibody (MPE8) that potently cross-neutralizes HRSV and HMPV as well as two animal paramyxoviruses: bovine RSV (BRSV) and pneumonia virus of mice (PVM). In its germline configuration, MPE8 is HRSV-specific and its breadth is achieved by somatic mutations in the light chain variable region. MPE8 did not result in the selection of viral escape mutants that evaded antibody targeting and showed potent prophylactic efficacy in animal models of HRSV and HMPV infection, as well as prophylactic and therapeutic efficacy in the more relevant model of lethal PVM infection. The core epitope of MPE8 was mapped on two highly conserved anti-parallel β-strands on the pre-fusion viral F protein, which are rearranged in the post-fusion F protein conformation. Twenty-six out of the thirty HRSV-specific neutralizing antibodies isolated were also found to be specific for the pre-fusion F protein. Taken together, these results indicate that MPE8 might be used for the prophylaxis and therapy of severe HRSV and HMPV infections and identify the pre-fusion F protein as a candidate HRSV vaccine.
doi: 10.1038/nature12442
構造生物学：eagドメインによるKCNHチャネル調節の構造的機構
The structural mechanism of KCNH-channel regulation by the eag domain p.444
The KCNH voltage-dependent potassium channels (ether-à-go-go, EAG; EAG-related gene, ERG; EAG-like channels, ELK) are important regulators of cellular excitability and have key roles in diseases such as cardiac long QT syndrome type 2 (LQT2), epilepsy, schizophrenia and cancer. The intracellular domains of KCNH channels are structurally distinct from other voltage-gated channels. The amino-terminal region contains an eag domain, which is composed of a Per-Arnt-Sim (PAS) domain and a PAS-cap domain, whereas the carboxy-terminal region contains a cyclic nucleotide-binding homology domain (CNBHD), which is connected to the pore through a C-linker domain. Many disease-causing mutations localize to these specialized intracellular domains, which underlie the unique gating and regulation of KCNH channels. It has been suggested that the eag domain may regulate the channel by interacting with either the S4–S5 linker or the CNBHD. Here we present a 2 Å resolution crystal structure of the eag domain–CNBHD complex of the mouse EAG1 (also known as KCNH1) channel. It displays extensive interactions between the eag domain and the CNBHD, indicating that the regulatory mechanism of the eag domain primarily involves the CNBHD. Notably, the structure reveals that a number of LQT2 mutations at homologous positions in human ERG, in addition to cancer-associated mutations in EAG channels, localize to the eag domain–CNBHD interface. Furthermore, mutations at the interface produced marked effects on channel gating, demonstrating the important physiological role of the eag domain–CNBHD interaction. Our structure of the eag domain–CNBHD complex of mouse EAG1 provides unique insights into the physiological and pathophysiological mechanisms of KCNH channels.
doi: 10.1038/nature12487
