네이처 컨텐츠

Editorials

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

전문

Book smart p.282

Novelist Thomas Pynchon shows that science and art can combine, with mutual benefit.

doi: 10.1038/501282b

전문

Spooked p.282

Researchers and lawmakers must work to rebuild trust in secure Internet standards.

doi: 10.1038/501282a

전문

News

Grass gets greener p.291

Plant secretion curbs greenhouse-gas emissions from soil.

Nicola Jones

doi: 10.1038/501291a

전문

News Features

Outlook for earth p.297

As the IPCC finalizes its next big climate-science assessment, Nature looks at the past and future of the planet's watchdog.

doi: 10.1038/501297a

전문

25 years of the IPCC p.298

A graphical tour through the history of the Intergovernmental Panel on Climate Change and the science that underlies it.

Nicola Jones

doi: 10.1038/501298a

전문

Rising tide p.300

Researchers struggle to project how fast, how high and how far the oceans will rise.

Nicola Jones

doi: 10.1038/501300a

전문

The climate chairman p.303

Getting hundreds of experts to agree is never easy. Ottmar Edenhofer takes a firm, philosophical approach to the task.

Quirin Schiermeier

doi: 10.1038/501303a

전문

News & Views

The cause of the pause p.318

A global climate model that factors in the observed temperature of the surface ocean in the eastern equatorial Pacific offers an explanation for the recent hiatus in global warming. See Letter p.403

Isaac M. Held

doi: 10.1038/501318a

전문

Miniature human brains p.319

A study shows that stem cells can be used to generate self-organizing three-dimensional tissues that mimic the developing human brain. These tissues provide a tool for modelling neurodevelopmental disorders. See Article p.373

Oliver Brüstle

doi: 10.1038/nature12552

전문

Mountain waves in the deep ocean p.321

Internal lee waves are a player in ocean dynamics that may make an important contribution to deep-ocean mixing. They warrant serious consideration for inclusion in the next generation of climate models.

Jennifer MacKinnon

doi: 10.1038/501321a

전문

Molecular one-upmanship p.322

Pathogens and their hosts engage in perpetual molecular arms races. In one such evolutionary stand-off, the protagonists are trypanosome parasites and a human immune complex based on a high-density lipoprotein. See Letter p.430

Jayne Raper & David J. Friedman

doi: 10.1038/501322a

전문

Fast-track solar cells p.323

The ultimate goal of the solar-cell industry is to make inexpensive devices that are highly efficient at converting sunlight into electricity. The advent of perovskite semiconductors could be the key to reaching this goal. See Letter p.395

Michael D. McGehee

doi: 10.1038/nature12557

전문

Down's syndrome link to ageing p.325

Triplication of the enzyme USP16 in models of Down's syndrome creates defects in the stem cells resident in adult tissues. This finding provides insight into stem-cell homeostasis during ageing. See Article p.380

George P. Souroullas & Norman E. Sharpless

doi: 10.1038/nature12558

전문

Articles

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.

Madeline A. Lancaster, Magdalena Renner, Carol-Anne Martin, Daniel Wenzel, Louise S. Bicknell, Matthew E. Hurles, Tessa Homfray, Josef M. Penninger, Andrew P. Jackson & Juergen A. Knoblich

doi: 10.1038/nature12517

전문 |PDF

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.

Maddalena Adorno, Shaheen Sikandar, Siddhartha S. Mitra, Angera Kuo, Benedetta Nicolis Di Robilant, Veronica Haro-Acosta, Youcef Ouadah, Marco Quarta, Jacqueline Rodriguez, Dalong Qian + et al.

doi: 10.1038/nature12530

전문 |PDF

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.

Nicholas Noinaj, Adam J. Kuszak, James C. Gumbart, Petra Lukacik, Hoshing Chang, Nicole C. Easley, Trevor Lithgow & Susan K. Buchanan

doi: 10.1038/nature12521

전문 |PDF

Letters

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.

R. P. Eatough, H. Falcke, R. Karuppusamy, K. J. Lee, D. J. Champion, E. F. Keane, G. Desvignes, D. H. F. M. Schnitzeler, L. G. Spitler, M. Kramer + et al.

doi: 10.1038/nature12499

전문 |PDF

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.

Mingzhen Liu, Michael B. Johnston & Henry J. Snaith

doi: 10.1038/nature12509

전문 |PDF

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.

Anil Desireddy, Brian E. Conn, Jingshu Guo, Bokwon Yoon, Robert N. Barnett, Bradley M. Monahan, Kristin Kirschbaum, Wendell P. Griffith, Robert L. Whetten, Uzi Landman + et al.

doi: 10.1038/nature12523

전문 |PDF

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.

Yu Kosaka & Shang-Ping Xie

doi: 10.1038/nature12534

전문 |PDF

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.

Andrew J. Watson, James R. Ledwell, Marie-José Messias, Brian A. King, Neill Mackay, Michael P. Meredith, Benjamin Mills & Alberto C. Naveira Garabato

doi: 10.1038/nature12432

전문 |PDF

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.

Jaime M. Ross, James B. Stewart, Erik Hagström, Stefan Brené, Arnaud Mourier, Giuseppe Coppotelli, Christoph Freyer, Marie Lagouge, Barry J. Hoffer, Lars Olson + et al.

doi: 10.1038/nature12474

전문 |PDF

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.

Maria A. Ermolaeva, Alexandra Segref, Alexander Dakhovnik, Hui-Ling Ou, Jennifer I. Schneider, Olaf Utermöhlen, Thorsten Hoppe & Björn Schumacher

doi: 10.1038/nature12452

전문 |PDF

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.

Jan R. Dörr, Yong Yu, Maja Milanovic, Gregor Beuster, Christin Zasada, J. Henry M. Däbritz, Jan Lisec, Dido Lenze, Anne Gerhardt, Katharina Schleicher + et al.

doi: 10.1038/nature12437

전문 |PDF

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.

S. Melanie Lee, Gregory P. Donaldson, Zbigniew Mikulski, Silva Boyajian, Klaus Ley & Sarkis K. Mazmanian

doi: 10.1038/nature12447

전문 |PDF

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.

Pierrick Uzureau, Sophie Uzureau, Laurence Lecordier, Frédéric Fontaine, Patricia Tebabi, Fabrice Homblé, Axelle Grélard, Vanessa Zhendre, Derek P. Nolan, Laurence Lins + et al.

doi: 10.1038/nature12516

전문 |PDF

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.

Masayuki Hirano, Peng Guo, Nathanael McCurley, Michael Schorpp, Sabyasachi Das, Thomas Boehm & Max D. Cooper

doi: 10.1038/nature12467

전문 |PDF

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.

Davide Corti, Siro Bianchi, Fabrizia Vanzetta, Andrea Minola, Laurent Perez, Gloria Agatic, Barbara Guarino, Chiara Silacci, Jessica Marcandalli, Benjamin J. Marsland + et al.

doi: 10.1038/nature12442

전문 |PDF

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.

Yoni Haitin, Anne E. Carlson & William N. Zagotta

doi: 10.1038/nature12487

전문 |PDF