Making the paper: Lei Jiang
Nature 463, 586 (2010). doi:10.1038/7281586a
Spider silk structure holds secret to catching water as well as flies.
Making the paper: Lei Jiang
Nature 463, 586 (2010). doi:10.1038/7281586a
Spider silk structure holds secret to catching water as well as flies.
Nature 463, 586 (2010). doi:10.1038/7281586b
Last authorRats have innate mapping ablities — scientists discovered in 2005 that the rodents maintain a grid-like map of their location by means of a network of brain neurons dubbed 'grid cells'. These cells have also been found in mice, but whether a similar
Nature 463, 586 (2010). doi:10.1038/7281586c
Two recent blog posts discuss science onscreen. If you didn't read Nature's cover article last week about the forces generated by barefoot runners, you can catch the latest film at Nature Video on the Great Beyond, a clip by the Barefoot Professor (http://go.nature.com/tPTQlH
Nature 463, 587 (2010). doi:10.1038/463587a
The complexity of genetic regulation is one of the great wonders of nature, but it represents a daunting challenge to unravel. The International Human Epigenome Consortium is an appropriate response.
Nature 463, 587 (2010). doi:10.1038/463587b
Science has done well in the proposed US budget. Researchers need to justify the funding boost.
Nature 463, 588 (2010). doi:10.1038/463588a
Researchers should be recognized for writing books to convey and develop science.
Nature 463, 590 (2010). doi:10.1038/463590a
Nature 463, 590 (2010). doi:10.1038/463590b
Nature 463, 590 (2010). doi:10.1038/463590c
Nature 463, 590 (2010). doi:10.1038/463590d
Science327, 566–571 (2010) 10.1126/science.1183602Many organic molecules are made up of multiple methylene units (–CH2–) in which the carbon–hydrogen bonds are inert to most reagents. Selectively converting just one of these methylenes into something else —
Nature 463, 590 (2010). doi:10.1038/463590e
Nature 463, 591 (2010). doi:10.1038/463591a
Nature 463, 591 (2010). doi:10.1038/463591b
Nature 463, 591 (2010). doi:10.1038/463591c
Nature 463, 591 (2010). doi:10.1038/463591d
Nature 463, 591 (2010). doi:10.1038/463591e
Author: Viola Vogel
A bioengineer discusses how mechanical forces in tissues may promote malignancy.The connective-tissue protein collagen has been considered to be a structural barrier against tumour invasion in tissues. Enzymes that cleave collagen and other extracellular matrix (ECM) molecules were thus thought to promote tumour progression,
Nature 463, 608 (2010). doi:10.1038/463608a
Author: Peter Turchin
The next decade is likely to be a period of growing instability in the United States and western Europe, which could undermine the sort of scientific progress you describe in the Opinion collection of '2020 visions' (Nature463, 26–32; 2010
Nature 463, 608 (2010). doi:10.1038/463608b
Author: Dietrich Leibfried
I believe that quantum simulation is slated for a breakthrough by 2020 (Nature463, 26–32; 2010). In a groundbreaking lecture (Intl J. Theor. Phys.21, 467–488; 1982), Richard Feynman pointed out that large
Nature 463, 608 (2010). doi:10.1038/463608c
Author: Siddharth Dasgupta
Tertiary education is poised for greater changes during the next decade than John Hennessey's vision implies (Nature463, 26–32; 2010). The rising demand for university education in the developing world could affect universities in developed countries.Western universities, for
Nature 463, 608 (2010). doi:10.1038/463608d
Authors: Nancy C. Andrews, Sally Kornbluth & Doug Stokke
A disappointing myopia seems to have afflicted your '2020 visions' (Nature463, 26–32; 2010), with just one female among the 20 contributors. This sends the wrong message at a time when women scientists are still striving for better representation.
Nature 463, 608 (2010). doi:10.1038/463608e
Author: Joan M. Herbers
In your prognostications about the future of science (Nature463, 26–32; 2010), you might have featured only women as authors, given that the ancient prophesying Sibyls were always female. However, there was just one woman among the twenty writers.
Nature 463, 610 (2010). doi:10.1038/463610a
Author: Steve Silberman
Steve Silberman enjoys a moving account that probes racial and ethical issues in medicine through the story of the young mother whose death from cancer led to the first immortal cell line.
Nature 463, 611 (2010). doi:10.1038/463611a
Author: Rodrigo Quian Quiroga
When Rodrigo Quian Quiroga visited Jorge Luis Borges's private library, he found annotated books that bear witness to the writer's fascination for memory and neuroscience.
Nature 463, 612 (2010). doi:10.1038/463612a
Author: Nicola Jones
The success of Peter Atkins's classic textbook Physical Chemistry led him to trade research for full-time writing and teaching in the 1980s. In the first of a series of five interviews with authors who each write science books for a different audience, Atkins explains how the rewards for textbooks can be great, but the effort needed can affect your research.
Nature 463, 613 (2010). doi:10.1038/463613a
Authors: David W. Krause
How, when and from where did Madagascar's unique mammalian fauna originate? The idea that the ancestors of that fauna rafted from Africa finds support in innovative simulations of ancient ocean currents.
Nature 463, 614 (2010). doi:10.1038/463614a
Authors: Rienk van Grondelle & Vladimir I. Novoderezhkin
The photosynthetic apparatus of cryptophyte algae is odd — its pigments are farther apart than is expected for efficient functioning. A study into how this apparatus works so well finds quantum effects at play.
Nature 463, 616 (2010). doi:10.1038/463616a
Authors: Frank J. Slack
Embryonic stem cells can create copies of themselves, but can also mature into almost any type of cell in the body. Tiny gene regulators called microRNAs are now shown to have a role in directing these properties.
Nature 463, 617 (2010). doi:10.1038/463617b
50 Years agoAlthough the problem of alcohol and road safety has been much in the public eye, there has hitherto been little precise evidence as to the effects of small quantities of alcohol on driving skill. For this reason, the careful study by Prof.
Nature 463, 617 (2010). doi:10.1038/463617a
Authors: Seth Redfield
The atmospheric properties of distant worlds are becoming increasingly clear. The latest observations reveal fluorescent emission from methane in the upper atmosphere of a Jupiter-like extrasolar planet.
Nature 463, 618 (2010). doi:10.1038/463618a
Author: Magdalena Helmer
Nature 463, 619 (2010). doi:10.1038/463619a
Authors: Rama Venkatasubramanian
The thermal process known as Joule heating, which often plagues electronic devices, has been turned to good use: making devices that can produce sound as well as reproduce music and speech.
Nature 463, 621 (2010). doi:10.1038/nature08725
Authors: Collin Melton, Robert L. Judson & Robert Blelloch
When embryonic stem cells (ESCs) differentiate, they must both silence the ESC self-renewal program and activate new tissue-specific programs. In the absence of DGCR8 (Dgcr8-/-), a protein required for microRNA (miRNA) biogenesis, mouse ESCs are unable to silence self-renewal. Here we show
Nature 463, 627 (2010). doi:10.1038/nature08728
Authors: Justin A. Boddey, Anthony N. Hodder, Svenja Günther, Paul R. Gilson, Heather Patsiouras, Eugene A. Kapp, J. Andrew Pearce, Tania F. de Koning-Ward, Richard J. Simpson, Brendan S. Crabb & Alan F. Cowman
Plasmodium falciparum causes the virulent form of malaria and disease manifestations are linked to growth inside infected erythrocytes. To survive and evade host responses the parasite remodels the erythrocyte by exporting several hundred effector proteins beyond the surrounding parasitophorous vacuole membrane. A feature of
Nature 463, 632 (2010). doi:10.1038/nature08726
Authors: Ilaria Russo, Shalon Babbitt, Vasant Muralidharan, Tamira Butler, Anna Oksman & Daniel E. Goldberg
During their intraerythrocytic development, malaria parasites export hundreds of proteins to remodel their host cell. Nutrient acquisition, cytoadherence and antigenic variation are among the key virulence functions effected by this erythrocyte takeover. Proteins destined for export are synthesized in the endoplasmic reticulum (ER) and cleaved
Nature 463, 637 (2010). doi:10.1038/nature08775
Authors: Mark R. Swain, Pieter Deroo, Caitlin A. Griffith, Giovanna Tinetti, Azam Thatte, Gautam Vasisht, Pin Chen, Jeroen Bouwman, Ian J. Crossfield, Daniel Angerhausen, Cristina Afonso & Thomas Henning
Detection of molecules using infrared spectroscopy probes the conditions and compositions of exoplanet atmospheres. Water (H2O), methane (CH4), carbon dioxide (CO2), and carbon monoxide (CO) have been detected in two hot Jupiters. These previous results relied on space-based telescopes that do not provide spectroscopic capability in the 2.4–5.2 μm spectral region. Here we report ground-based observations of the dayside emission spectrum for HD 189733b between 2.0–2.4 μm and 3.1–4.1 μm, where we find a bright emission feature. Where overlap with space-based instruments exists, our results are in excellent agreement with previous measurements. A feature at ∼3.25 μm is unexpected and difficult to explain with models that assume local thermodynamic equilibrium (LTE) conditions at the 1 bar to 1 × 10-6 bar pressures typically sampled by infrared measurements. The most likely explanation for this feature is that it arises from non-LTE emission from CH4, similar to what is seen in the atmospheres of planets in our own Solar System. These results suggest that non-LTE effects may need to be considered when interpreting measurements of strongly irradiated exoplanets.
Nature 463, 640 (2010). doi:10.1038/nature08729
Authors: Yongmei Zheng, Hao Bai, Zhongbing Huang, Xuelin Tian, Fu-Qiang Nie, Yong Zhao, Jin Zhai & Lei Jiang
Many biological surfaces in both the plant and animal kingdom possess unusual structural features at the micro- and nanometre-scale that control their interaction with water and hence wettability. An intriguing example is provided by desert beetles, which use micrometre-sized patterns of hydrophobic and hydrophilic regions on their backs to capture water from humid air. As anyone who has admired spider webs adorned with dew drops will appreciate, spider silk is also capable of efficiently collecting water from air. Here we show that the water-collecting ability of the capture silk of the cribellate spider Uloborus walckenaerius is the result of a unique fibre structure that forms after wetting, with the ‘wet-rebuilt’ fibres characterized by periodic spindle-knots made of random nanofibrils and separated by joints made of aligned nanofibrils. These structural features result in a surface energy gradient between the spindle-knots and the joints and also in a difference in Laplace pressure, with both factors acting together to achieve continuous condensation and directional collection of water drops around spindle-knots. Submillimetre-sized liquid drops have been driven by surface energy gradients or a difference in Laplace pressure, but until now neither force on its own has been used to overcome the larger hysteresis effects that make the movement of micrometre-sized drops more difficult. By tapping into both driving forces, spider silk achieves this task. Inspired by this finding, we designed artificial fibres that mimic the structural features of silk and exhibit its directional water-collecting ability.
Nature 463, 644 (2010). doi:10.1038/nature08811
Authors: Elisabetta Collini, Cathy Y. Wong, Krystyna E. Wilk, Paul M. G. Curmi, Paul Brumer & Gregory D. Scholes
Photosynthesis makes use of sunlight to convert carbon dioxide into useful biomass and is vital for life on Earth. Crucial components for the photosynthetic process are antenna proteins, which absorb light and transmit the resultant excitation energy between molecules to a reaction centre. The efficiency of these electronic energy transfers has inspired much work on antenna proteins isolated from photosynthetic organisms to uncover the basic mechanisms at play. Intriguingly, recent work has documented that light-absorbing molecules in some photosynthetic proteins capture and transfer energy according to quantum-mechanical probability laws instead of classical laws at temperatures up to 180 K. This contrasts with the long-held view that long-range quantum coherence between molecules cannot be sustained in complex biological systems, even at low temperatures. Here we present two-dimensional photon echo spectroscopy measurements on two evolutionarily related light-harvesting proteins isolated from marine cryptophyte algae, which reveal exceptionally long-lasting excitation oscillations with distinct correlations and anti-correlations even at ambient temperature. These observations provide compelling evidence for quantum-coherent sharing of electronic excitation across the 5-nm-wide proteins under biologically relevant conditions, suggesting that distant molecules within the photosynthetic proteins are ‘wired’ together by quantum coherence for more efficient light-harvesting in cryptophyte marine algae.
Nature 463, 648 (2010). doi:10.1038/nature08755
Authors: David R. Shelly
The San Andreas fault is one of the most extensively studied faults in the world, yet its physical character and deformation mode beneath the relatively shallow earthquake-generating portion remain largely unconstrained. Tectonic ‘non-volcanic’ tremor, a recently discovered seismic signal probably generated by shear slip on the deep extension of some major faults, can provide new insight into the deep fate of such faults, including that of the San Andreas fault near Parkfield, California. Here I examine continuous seismic data from mid-2001 to 2008, identifying tremor and decomposing the signal into different families of activity based on the shape and timing of the waveforms at multiple stations. This approach allows differentiation between activities from nearby patches of the deep fault and begins to unveil rich and complex patterns of tremor occurrence. I find that tremor exhibits nearly continuous migration, with the most extensive episodes propagating more than 20 kilometres along fault strike at rates of 15–80 kilometres per hour. This suggests that the San Andreas fault remains a localized through-going structure, at least to the base of the crust, in this area. Tremor rates and recurrence behaviour changed markedly in the wake of the 2004 magnitude-6.0 Parkfield earthquake, but these changes were far from uniform within the tremor zone, probably reflecting heterogeneous fault properties and static and dynamic stresses decaying away from the rupture. The systematic recurrence of tremor demonstrated here suggests the potential to monitor detailed time-varying deformation on this portion of the deep San Andreas fault, deformation which unsteadily loads the shallower zone that last ruptured in the 1857 magnitude-7.9 Fort Tejon earthquake.
Nature 463, 653 (2010). doi:10.1038/nature08706
Authors: Jason R. Ali & Matthew Huber
Madagascar hosts one of the world’s most unusual, endemic, diverse and threatened concentrations of fauna. To explain its unique, imbalanced biological diversity, G. G. Simpson proposed the ‘sweepstakes hypothesis’, according to which the ancestors of Madagascar’s present-day mammal stock rafted there from Africa. This is an important hypothesis in biogeography and evolutionary theory for how animals colonize new frontiers, but its validity is questioned. Studies suggest that currents were inconsistent with rafting to Madagascar and that land bridges provided the migrants’ passage. Here we show that currents could have transported the animals to the island and highlight evidence inconsistent with the land-bridge hypothesis. Using palaeogeographic reconstructions and palaeo-oceanographic modelling, we find that strong surface currents flowed from northeast Mozambique and Tanzania eastward towards Madagascar during the Palaeogene period, exactly as required by the ‘sweepstakes process’. Subsequently, Madagascar advanced north towards the equatorial gyre and the regional current system evolved into its modern configuration with flows westward from Madagascar to Africa. This may explain why no fully non-aquatic land mammals have colonized Madagascar since the arrival of the rodents and carnivorans during the early-Miocene epoch. One implication is that rafting may be the dominant means of overseas dispersal in the Cenozoic era when palaeocurrent directions are properly considered.
Nature 463, 657 (2010). doi:10.1038/nature08704
Authors: Christian F. Doeller, Caswell Barry & Neil Burgess
Grid cells in the entorhinal cortex of freely moving rats provide a strikingly periodic representation of self-location which is indicative of very specific computational mechanisms. However, the existence of grid cells in humans and their distribution throughout the brain are unknown. Here we show that the preferred firing directions of directionally modulated grid cells in rat entorhinal cortex are aligned with the grids, and that the spatial organization of grid-cell firing is more strongly apparent at faster than slower running speeds. Because the grids are also aligned with each other, we predicted a macroscopic signal visible to functional magnetic resonance imaging (fMRI) in humans. We then looked for this signal as participants explored a virtual reality environment, mimicking the rats’ foraging task: fMRI activation and adaptation showing a speed-modulated six-fold rotational symmetry in running direction. The signal was found in a network of entorhinal/subicular, posterior and medial parietal, lateral temporal and medial prefrontal areas. The effect was strongest in right entorhinal cortex, and the coherence of the directional signal across entorhinal cortex correlated with spatial memory performance. Our study illustrates the potential power of combining single-unit electrophysiology with fMRI in systems neuroscience. Our results provide evidence for grid-cell-like representations in humans, and implicate a specific type of neural representation in a network of regions which supports spatial cognition and also autobiographical memory.
Nature 463, 662 (2010). doi:10.1038/nature08739
Authors: Valeria Specchia, Lucia Piacentini, Patrizia Tritto, Laura Fanti, Rosalba D’Alessandro, Gioacchino Palumbo, Sergio Pimpinelli & Maria P. Bozzetti
The canalization concept describes the resistance of a developmental process to phenotypic variation, regardless of genetic and environmental perturbations, owing to the existence of buffering mechanisms. Severe perturbations, which overcome such buffering mechanisms, produce altered phenotypes that can be heritable and can themselves be canalized by a genetic assimilation process. An important implication of this concept is that the buffering mechanism could be genetically controlled. Recent studies on Hsp90, a protein involved in several cellular processes and development pathways, indicate that it is a possible molecular mechanism for canalization and genetic assimilation. In both flies and plants, mutations in the Hsp90-encoding gene induce a wide range of phenotypic abnormalities, which have been interpreted as an increased sensitivity of different developmental pathways to hidden genetic variability. Thus, Hsp90 chaperone machinery may be an evolutionarily conserved buffering mechanism of phenotypic variance, which provides the genetic material for natural selection. Here we offer an additional, perhaps alternative, explanation for proposals of a concrete mechanism underlying canalization. We show that, in Drosophila, functional alterations of Hsp90 affect the Piwi-interacting RNA (piRNA; a class of germ-line-specific small RNAs) silencing mechanism leading to transposon activation and the induction of morphological mutants. This indicates that Hsp90 mutations can generate new variation by transposon-mediated ‘canonical’ mutagenesis.
Nature 463, 666 (2010). doi:10.1038/nature08689
Authors: Elena G. Bochukova, Ni Huang, Julia Keogh, Elana Henning, Carolin Purmann, Kasia Blaszczyk, Sadia Saeed, Julian Hamilton-Shield, Jill Clayton-Smith, Stephen O’Rahilly, Matthew E. Hurles & I. Sadaf Farooqi
Obesity is a highly heritable and genetically heterogeneous disorder. Here we investigated the contribution of copy number variation to obesity in 300 Caucasian patients with severe early-onset obesity, 143 of whom also had developmental delay. Large (>500 kilobases), rare (<1%) deletions were significantly enriched in patients compared to 7,366 controls (P < 0.001). We identified several rare copy number variants that were recurrent in patients but absent or at much lower prevalence in controls. We identified five patients with overlapping deletions on chromosome 16p11.2 that were found in 2 out of 7,366 controls (P < 5 × 10-5). In three patients the deletion co-segregated with severe obesity. Two patients harboured a larger de novo 16p11.2 deletion, extending through a 593-kilobase region previously associated with autism and mental retardation; both of these patients had mild developmental delay in addition to severe obesity. In an independent sample of 1,062 patients with severe obesity alone, the smaller 16p11.2 deletion was found in an additional two patients. All 16p11.2 deletions encompass several genes but include SH2B1, which is known to be involved in leptin and insulin signalling. Deletion carriers exhibited hyperphagia and severe insulin resistance disproportionate for the degree of obesity. We show that copy number variation contributes significantly to the genetic architecture of human obesity.
Nature 463, 671 (2010). doi:10.1038/nature08727
Authors: R. G. Walters, S. Jacquemont, A. Valsesia, A. J. de Smith, D. Martinet, J. Andersson, M. Falchi, F. Chen, J. Andrieux, S. Lobbens, B. Delobel, F. Stutzmann, J. S. El-Sayed Moustafa, J.-C. Chèvre, C. Lecoeur, V. Vatin, S. Bouquillon, J. L. Buxton, O. Boute, M. Holder-Espinasse, J.-M. Cuisset, M.-P. Lemaitre, A.-E. Ambresin, A. Brioschi, M. Gaillard, V. Giusti, F. Fellmann, A. Ferrarini, N. Hadjikhani, D. Campion, A. Guilmatre, A. Goldenberg, N. Calmels, J.-L. Mandel, C. Le Caignec, A. David, B. Isidor, M.-P. Cordier, S. Dupuis-Girod, A. Labalme, D. Sanlaville, M. Béri-Dexheimer, P. Jonveaux, B. Leheup, K. Õunap, E. G. Bochukova, E. Henning, J. Keogh, R. J. Ellis, K. D. MacDermot, M. M. van Haelst, C. Vincent-Delorme, G. Plessis, R. Touraine, A. Philippe, V. Malan, M. Mathieu-Dramard, J. Chiesa, B. Blaumeiser, R. F. Kooy, R. Caiazzo, M. Pigeyre, B. Balkau, R. Sladek, S. Bergmann, V. Mooser, D. Waterworth, A. Reymond, P. Vollenweider, G. Waeber, A. Kurg, P. Palta, T. Esko, A. Metspalu, M. Nelis, P. Elliott, A.-L. Hartikainen, M. I. McCarthy, L. Peltonen, L. Carlsson, P. Jacobson, L. Sjöström, N. Huang, M. E. Hurles, S. O’Rahilly, I. S. Farooqi, K. Männik, M.-R. Jarvelin, F. Pattou, D. Meyre, A. J. Walley, L. J. M. Coin, A. I. F. Blakemore, P. Froguel & J. S. Beckmann
Obesity has become a major worldwide challenge to public health, owing to an interaction between the Western ‘obesogenic’ environment and a strong genetic contribution. Recent extensive genome-wide association studies (GWASs) have identified numerous single nucleotide polymorphisms associated with obesity, but these loci together account for only a small fraction of the known heritable component. Thus, the ‘common disease, common variant’ hypothesis is increasingly coming under challenge. Here we report a highly penetrant form of obesity, initially observed in 31 subjects who were heterozygous for deletions of at least 593 kilobases at 16p11.2 and whose ascertainment included cognitive deficits. Nineteen similar deletions were identified from GWAS data in 16,053 individuals from eight European cohorts. These deletions were absent from healthy non-obese controls and accounted for 0.7% of our morbid obesity cases (body mass index (BMI) ≥ 40 kg m-2 or BMI standard deviation score ≥ 4; P = 6.4 × 10-8, odds ratio 43.0), demonstrating the potential importance in common disease of rare variants with strong effects. This highlights a promising strategy for identifying missing heritability in obesity and other complex traits: cohorts with extreme phenotypes are likely to be enriched for rare variants, thereby improving power for their discovery. Subsequent analysis of the loci so identified may well reveal additional rare variants that further contribute to the missing heritability, as recently reported for SIM1 (ref. 3). The most productive approach may therefore be to combine the ‘power of the extreme’ in small, well-phenotyped cohorts, with targeted follow-up in case-control and population cohorts.
Nature 463, 676 (2010). doi:10.1038/nature08734
Authors: Kazuhito Naka, Takayuki Hoshii, Teruyuki Muraguchi, Yuko Tadokoro, Takako Ooshio, Yukio Kondo, Shinji Nakao, Noboru Motoyama & Atsushi Hirao
Chronic myeloid leukaemia (CML) is caused by a defined genetic abnormality that generates BCR-ABL, a constitutively active tyrosine kinase. It is widely believed that BCR-ABL activates Akt signalling that suppresses the forkhead O transcription factors (FOXO), supporting the proliferation or inhibiting the apoptosis of CML cells. Although the use of the tyrosine kinase inhibitor imatinib is a breakthrough for CML therapy, imatinib does not deplete the leukaemia-initiating cells (LICs) that drive the recurrence of CML. Here, using a syngeneic transplantation system and a CML-like myeloproliferative disease mouse model, we show that Foxo3a has an essential role in the maintenance of CML LICs. We find that cells with nuclear localization of Foxo3a and decreased Akt phosphorylation are enriched in the LIC population. Serial transplantation of LICs generated from Foxo3a+/+ and Foxo3a-/- mice shows that the ability of LICs to cause disease is significantly decreased by Foxo3a deficiency. Furthermore, we find that TGF-β is a critical regulator of Akt activation in LICs and controls Foxo3a localization. A combination of TGF-β inhibition, Foxo3a deficiency and imatinib treatment led to efficient depletion of CML in vivo. Furthermore, the treatment of human CML LICs with a TGF-β inhibitor impaired their colony-forming ability in vitro. Our results demonstrate a critical role for the TGF-β–FOXO pathway in the maintenance of LICs, and strengthen our understanding of the mechanisms that specifically maintain CML LICs in vivo.
Nature 463, 681 (2010). doi:10.1038/nature08717
Authors: Sergey V. Solomatin, Max Greenfeld, Steven Chu & Daniel Herschlag
According to the ‘thermodynamic hypothesis’, the sequence of a biological macromolecule defines its folded, active (or ‘native’) structure as a global energy minimum in the folding landscape. However, the enormous complexity of folding landscapes of large macromolecules raises the question of whether there is in fact a unique global minimum corresponding to a unique native conformation or whether there are deep local minima corresponding to alternative active conformations. The folding of many proteins is well described by two-state models, leading to highly simplified representations of protein folding landscapes with a single native conformation. Nevertheless, accumulating experimental evidence suggests a more complex topology of folding landscapes with multiple active conformations that can take seconds or longer to interconvert. Here we demonstrate, using single-molecule experiments, that an RNA enzyme folds into multiple distinct native states that interconvert on a timescale much longer than that of catalysis. These data demonstrate that severe ruggedness of RNA folding landscapes extends into conformational space occupied by native conformations.
Nature 463, 685 (2010). doi:10.1038/nature08743
Authors: Beth G. Wensley, Sarah Batey, Fleur A. C. Bone, Zheng Ming Chan, Nuala R. Tumelty, Annette Steward, Lee Gyan Kwa, Alessandro Borgia & Jane Clarke
Energy landscape theory is a powerful tool for understanding the structure and dynamics of complex molecular systems, in particular biological macromolecules. The primary sequence of a protein defines its free-energy landscape and thus determines the folding pathway and the rate constants of folding and unfolding, as well as the protein’s native structure. Theory has shown that roughness in the energy landscape will lead to slower folding, but derivation of detailed experimental descriptions of this landscape is challenging. Simple folding models show that folding is significantly influenced by chain entropy; proteins in which the contacts are local fold quickly, owing to the low entropy cost of forming stabilizing, native contacts during folding. For some protein families, stability is also a determinant of folding rate constants. Where these simple metrics fail to predict folding behaviour, it is probable that there are features in the energy landscape that are unusual. Such general observations cannot explain the folding behaviour of the R15, R16 and R17 domains of α-spectrin. R15 folds ∼3,000 times faster than its homologues, although they have similar structures, stabilities and, as far as can be determined, transition-state stabilities. Here we show that landscape roughness (internal friction) is responsible for the slower folding and unfolding of R16 and R17. We use chimaeric domains to demonstrate that this internal friction is a property of the core, and suggest that frustration in the landscape of the slow-folding spectrin domains may be due to misdocking of the long helices during folding. Theoretical studies have suggested that rugged landscapes will result in slower folding; here we show experimentally that such a phenomenon directly influences the folding kinetics of a ‘normal’ protein, that is, one with a significant energy barrier that folds on a relatively slow, millisecond–second, timescale.
Nature 463, 689 (2010). doi:10.1038/nature08722
Authors: Sarah D. Cady, Klaus Schmidt-Rohr, Jun Wang, Cinque S. Soto, William F. DeGrado & Mei Hong
The M2 protein of influenza A virus is a membrane-spanning tetrameric proton channel targeted by the antiviral drugs amantadine and rimantadine. Resistance to these drugs has compromised their effectiveness against many influenza strains, including pandemic H1N1. A recent crystal structure of M2(22–46) showed electron densities attributed to a single amantadine in the amino-terminal half of the pore, indicating a physical occlusion mechanism for inhibition. However, a solution NMR structure of M2(18–60) showed four rimantadines bound to the carboxy-terminal lipid-facing surface of the helices, suggesting an allosteric mechanism. Here we show by solid-state NMR spectroscopy that two amantadine-binding sites exist in M2 in phospholipid bilayers. The high-affinity site, occupied by a single amantadine, is located in the N-terminal channel lumen, surrounded by residues mutated in amantadine-resistant viruses. Quantification of the protein–amantadine distances resulted in a 0.3 Å-resolution structure of the high-affinity binding site. The second, low-affinity, site was observed on the C-terminal protein surface, but only when the drug reaches high concentrations in the bilayer. The orientation and dynamics of the drug are distinct in the two sites, as shown by 2H NMR. These results indicate that amantadine physically occludes the M2 channel, thus paving the way for developing new antiviral drugs against influenza viruses. The study demonstrates the ability of solid-state NMR to elucidate small-molecule interactions with membrane proteins and determine high-resolution structures of their complexes.
Nature 463, 700 (2010). doi:10.1038/463700a
Author: T. F. Davenport
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