Volume 492 Issue 7428

Editorials

Words are not enough p.153

The political inertia that characterizes the world’s response to global warming cannot continue. Politicians and policy-makers must follow the climate’s lead — and change.

doi: 10.1038/492153a

Life on land p.153

Evidence for the first land life is controversial, but the fossil record has a tendency to surprise.

doi: 10.1038/492153b

News

News Features

Feeling the heat p.174

The more that microcircuits are shrunk, the hotter they get. Engineers are on the hunt for ways to cool off computing.

doi: 10.1038/492174a

News & Views

SynthesisA constructive debate p.188

Synthetic chemistry has long been used to prepare useful compounds — especially those that are hard to obtain from natural sources. But synthetic biology is coming of age as an alternative strategy. A biologist and two chemists debate the merits of their fields' synthetic prowess.

doi: 10.1038/492188a

Cell biologyAll clear for ribosome landing p.189

The discovery of a dramatic structural rearrangement that is stabilized by an RNA scaffold helps to explain how nascent proteins are delivered for export from the cell cytoplasm. See Letter p.271

doi: 10.1038/492189a

AstrophysicsA pas de trois birth for wide binary stars p.191

The widest binary star systems pose a challenge to theory: true stellar twins could not form so far apart. Simulations suggest these twins are in fact triplets, two of which masquerade as one star and cast out the third. See Letter p.221

doi: 10.1038/nature11762

AstronomyClearing up the dust p.192

Constructing the history of star formation over cosmic time requires an understanding of how starlight is absorbed by dust in galaxies. It now seems that there is less universality in such absorption across galaxies than expected.

doi: 10.1038/492192a

EconomicsConservation in the red p.193

The Convention on Biological Diversity has pledged to reduce species-extinction threats around the globe by 2020. Analysis shows that this goal is achievable but requires a significant increase in the current rate of investment.

doi: 10.1038/492193a

Cell biologyDeath by deacetylation p.194

Necrosis is associated with various diseases, yet it is arguably the least-understood form of programmed cell death. It emerges that a sirtuin protein regulates one form of necrosis through a deacetylation reaction. See Article p.199

doi: 10.1038/nature11761

BiochemistryMolecular hurdles cleared with ease p.195

Single-molecule studies reveal that a ring-like enzyme that encircles and 'slides' along one strand of duplex DNA, separating it from the other strand, overcomes molecular barriers in its path by transiently opening its ring. See Article p.205

doi: 10.1038/nature11758

Applied physicsMolecules that convert heat into light p.197

A class of fluorescent organic molecule has been designed that enables highly efficient light-emitting diodes to be made. The devices may turn out to be competitors to their conventional analogues. See Letter p.234

doi: 10.1038/492197a

Articles

The NAD-dependent deacetylase SIRT2 is required for programmed necrosis p.199

Although initially viewed as unregulated, increasing evidence suggests that cellular necrosis often proceeds through a specific molecular program. In particular, death ligands such as tumour necrosis factor (TNF)-α activate necrosis by stimulating the formation of a complex containing receptor-interacting protein 1 (RIP1) and receptor-interacting protein 3 (RIP3). Relatively little is known regarding how this complex formation is regulated. Here, we show that the NAD-dependent deacetylase SIRT2 binds constitutively to RIP3 and that deletion or knockdown of SIRT2 prevents formation of the RIP1–RIP3 complex in mice. Furthermore, genetic or pharmacological inhibition of SIRT2 blocks cellular necrosis induced by TNF-α. We further demonstrate that RIP1 is a critical target of SIRT2-dependent deacetylation. Using gain- and loss-of-function mutants, we demonstrate that acetylation of RIP1 lysine 530 modulates RIP1–RIP3 complex formation and TNF-α-stimulated necrosis. In the setting of ischaemia-reperfusion injury, RIP1 is deacetylated in a SIRT2-dependent fashion. Furthermore, the hearts of Sirt2−/− mice, or wild-type mice treated with a specific pharmacological inhibitor of SIRT2, show marked protection from ischaemic injury. Taken together, these results implicate SIRT2 as an important regulator of programmed necrosis and indicate that inhibitors of this deacetylase may constitute a novel approach to protect against necrotic injuries, including ischaemic stroke and myocardial infarction.

doi: 10.1038/nature11700

Bypass of a protein barrier by a replicative DNA helicase p.205

Replicative DNA helicases generally unwind DNA as a single hexamer that encircles and translocates along one strand of the duplex while excluding the complementary strand (known as steric exclusion). By contrast, large T antigen, the replicative DNA helicase of the simian virus 40 (SV40), is reported to function as a pair of stacked hexamers that pumps double-stranded DNA through its central channel while laterally extruding single-stranded DNA. Here we use single-molecule and ensemble assays to show that large T antigen assembled on the SV40 origin unwinds DNA efficiently as a single hexamer that translocates on single-stranded DNA in the 3′-to-5′ direction. Unexpectedly, large T antigen unwinds DNA past a DNA–protein crosslink on the translocation strand, suggesting that the large T antigen ring can open to bypass bulky adducts. Together, our data underscore the profound conservation among replicative helicase mechanisms, and reveal a new level of plasticity in the interactions of replicative helicases with DNA damage.

doi: 10.1038/nature11730

Structure of the TatC core of the twin-arginine protein transport system p.210

The twin-arginine translocation (Tat) pathway is one of two general protein transport systems found in the prokaryotic cytoplasmic membrane and is conserved in the thylakoid membrane of plant chloroplasts. The defining, and highly unusual, property of the Tat pathway is that it transports folded proteins, a task that must be achieved without allowing appreciable ion leakage across the membrane. The integral membrane TatC protein is the central component of the Tat pathway. TatC captures substrate proteins by binding their signal peptides. TatC then recruits TatA family proteins to form the active translocation complex. Here we report the crystal structure of TatC from the hyperthermophilic bacterium Aquifex aeolicus. This structure provides a molecular description of the core of the Tat translocation system and a framework for understanding the unique Tat transport mechanism.

doi: 10.1038/nature11683

Automated design of ligands to polypharmacological profiles p.215

The clinical efficacy and safety of a drug is determined by its activity profile across many proteins in the proteome. However, designing drugs with a specific multi-target profile is both complex and difficult. Therefore methods to design drugs rationally a priori against profiles of several proteins would have immense value in drug discovery. Here we describe a new approach for the automated design of ligands against profiles of multiple drug targets. The method is demonstrated by the evolution of an approved acetylcholinesterase inhibitor drug into brain-penetrable ligands with either specific polypharmacology or exquisite selectivity profiles for G-protein-coupled receptors. Overall, 800 ligand–target predictions of prospectively designed ligands were tested experimentally, of which 75% were confirmed to be correct. We also demonstrate target engagement in vivo. The approach can be a useful source of drug leads when multi-target profiles are required to achieve either selectivity over other drug targets or a desired polypharmacology.

doi: 10.1038/nature11691

Letters

An unexpectedly low oscillator strength as the origin of the Fe xvii emission problem p.225

Fluorescence of iron ions induced by an X-ray laser allows the relative oscillator strength for Fe xvii emission to be determined; it is found to differ by 3.6σ from the best quantum mechanical calculations, suggesting that the poor agreement between prediction and observations of the brightest Fe xvii line is rooted in the quality of the underlying atomic wavefunctions used in the models.

doi: 10.1038/nature11627

Highly efficient organic light-emitting diodes from delayed fluorescence p.234

A class of metal-free organic electroluminescent molecules is designed in which both singlet and triplet excitons contribute to light emission, leading to an intrinsic fluorescence efficiency greater than 90 per cent and an external electroluminescence efficiency comparable to that achieved in high-efficiency phosphorescence-based organic light-emitting diodes.

doi: 10.1038/nature11687

Increased future ice discharge from Antarctica owing to higher snowfall p.239

Climate models predict that precipitation will increase in Antarctica, leading to potential ice mass gain and an offset to sea level rise, but here it is shown that enhanced snowfall on Antarctica is likely to increase ice discharge and thereby negate 30% to 65% of the snowfall-induced ice gain.

doi: 10.1038/nature11616

Activated GTPase movement on an RNA scaffold drives co-translational protein targeting p.271

Single-molecule fluorescence microscopy techniques are used to elucidate features of the highly conserved protein-targeting machinery known as the signal recognition particle (SRP); the long SRP RNA is shown to be crucial for correct timing and precision of cargo handover to the protein-translocation machinery, a finding that could help to explain how other ribonucleosome complexes function during complex cellular processes.

doi: 10.1038/nature11726

Regulation of ISWI involves inhibitory modules antagonized by nucleosomal epitopes p.280

Two separate regulatory regions on the Drosophila chromatin remodeller ISWI are defined, AutoN and NegC, which negatively regulate ATP hydrolysis and the coupling of ATP hydrolysis to productive DNA translocation, respectively; epitopes on nucleosomes activate ISWI by inhibiting these negative regulatory domains, ensuring that remodelling occurs only in the appropriate chromatin context.

doi: 10.1038/nature11625