Research articles

Lipid asymmetry can be disrupted during biological processes such as apoptosis, during which phosphatidylserine in the inner leaflet of the membrane is exposed on the outer membrane. It has been proposed that activation of a phospholipid scramblase catalyses bidirectional transbilayer movement of phospholipids, but the protein corresponding to this activity has not been identified. Here, the protein TMEM16F is identified, and is an essential component for the Ca²⁺-dependent exposure of phosphatidylserine on the plasma membrane. A patient with Scott syndrome, which results from a defect in phospholipid scrambling activity, was found to carry a mutation in the gene encoding TMEM16F.

Focal adhesions link the extracellular matrix by integrin receptors to cytoplasmic actin filaments and are fundamental to human physiology. These authors determine the molecular architecture of focal adhesions by mapping protein organization at the nanoscale level. The results demonstrate that focal adhesions possess a well-organized ultrastructure made up of at least three spatial and functional compartments that mediate their interdependent functions.

In cells, WAVE protein, a central regulator of actin dynamics during cell motility, is constitutively incorporated into WAVE regulatory complex (WRC), is normally present in an inactive state and can be activated by a number of inputs. These authors present the structure and mechanistic analysis of WRC. The combined data reveal how the WAVE protein is inhibited within the WRC complex and provide mechanisms for WRC activation at the plasma membrane.

The anaphase promoting complex/cyclosome (APC/C) is a large multimeric ubiquitin E3 ligase that regulates the eukaryotic cell cycle in processes such as chromatid segregation and completion of mitosis. It catalyses the polyubiquitylation of a diverse array of mitotic regulatory proteins and targets them for proteasomal degradation. Target selection also involves a co-activator protein (either Cdc20 or Cdh1) together with core APC/C subunits. Here, a cryo-EM structure of APC/C^Chd1 bound to a D-box peptide substrate is presented. The structure provides important insight into the recognition and catalytic mechanism of APC/C substrates.

Recent data from early clinical trials in melanoma patients carrying mutations in the B-RAF gene have shown promising results with the B-RAF kinase inhibitor PLX4032; however, many patients eventually develop resistance to this treatment. Two papers now uncover possible mechanisms of resistance to PLX4032. One paper shows that upregulation of MAP3K8 (which encodes COT) can confer resistance of melanoma cells to B-RAF inhibitors, whereas another paper found that melanomas can acquire resistance due to mutations of N-RAS or increased expression of PDGFRβ. Each of these resistance mechanisms seems to apply to at least some patients on recent PLX4032 trial, whereas, surprisingly, so far no secondary B-RAF mutations have been observed.

Sugar efflux transporters are essential for diverse processes such as nectar production and seed and pollen development, as well for the maintenance of blood glucose levels in animals. These authors identify and characterize a novel sugar transporter family, SWEET, and show that several Arabidopsis, rice and metazoan homologues mediate glucose transport. In addition, some of these transporters are exploited by plant pathogens for nutritional gain and virulence.

Recent data from early clinical trials in melanoma patients carrying mutations in the B-RAF gene have shown promising results with the B-RAF kinase inhibitor PLX4032; however, many patients eventually develop resistance to this treatment. Two papers now uncover possible mechanisms of resistance to PLX4032. One paper shows that upregulation of MAP3K8 (which encodes COT) can confer resistance of melanoma cells to B-RAF inhibitors, whereas another paper found that melanomas can acquire resistance due to mutations of N-RAS or increased expression of PDGFRβ. Each of these resistance mechanisms seems to apply to at least some patients on recent PLX4032 trial, whereas, surprisingly, so far no secondary B-RAF mutations have been observed.

The kinetochore is a large protein complex that assembles on centromeric DNA and captures microtubules to mediate chromosome separation. These authors report the first purification of functional kinetochores. They also show that kinetochore particles maintain load-bearing associations with assembling and disassembling ends of single microtubules and that tension increases the lifetimes of the attachments directly. These results provide evidence that tension selectively stabilises kinetochore–microtubule interactions.

This is one of two papers showing that glioblastoma cells can differentiate into functional endothelial cells as part of the tumour vasculature. These endothelial cells are characterized by the same genetic alterations as the glioblastoma cells. The tumour-derived endothelial cells originate in putative glioblastoma-initiating cells and are functionally important for tumorigenesis.

This is one of two papers showing that glioblastoma cells can differentiate into functional endothelial cells as part of the tumour vasculature. These endothelial cells are characterized by the same genetic alterations as the glioblastoma cells. The tumour-derived endothelial cells originate in putative glioblastoma-initiating cells and are functionally important for tumorigenesis.

Some beetle shells exhibit iridescence owing to the chiral organization of chitin making up the beetle's exoskeleton. Inspired by this, these authors fabricate thin glass films with helical pores introduced using a renewable cellulose template. The chiral structure allows the material, which can be free-standing, to selectively reflect light at a specific wavelength that can be tuned across the visible spectrum by altering the ratio of silica to cellulose during synthesis.

Long interspersed nuclear elements-1 (L1) retrotransposons affect gene expression and neuronal function throughout brain development. These authors show that the absence of methyl-CpG-binding protein 2, a modulator of DNA methylation implicated in several neurodevelopmental disorders, increases L1 retrotransposon activity in rodent models, with this increase in susceptibility duplicated in patients with Rett syndrome. These correlations suggest that disease-related genetic mutations may influence L1 retrotransposon activity.

Many cellular and virus messenger RNAs are methylated at the 2′-O positions of the 5′ guanosine cap. The role of 2′-O methylation in virus infection has been unclear. These authors show that this form of methylation enables several unrelated viruses to evade the antiviral effects of genes stimulated by type I interferon.

Contact-dependent growth inhibition (CDI) through a two-component system was first described in Escherichia coli as a mechanism to inhibit growth of bacterial cells that do not possess this system. Now the widespread occurrence of CDI in bacteria and the molecular basis for some of these interactions have been elucidated. The data suggest that CDI is a common mechanism by which microbes compete with each other in the environment.

The health of marine ecosystems is traditionally assessed by measuring the mean trophic level (MTL) of fishery catches. These authors model catch MTL and actual ecosystem MTL, and show that the former is not a good measure of the latter. They then show that MTLs have actually been increasing in recent years, but that fisheries are still at risk of collapse because all trophic levels have been similarly affected.

Reprogramming of X-chromosome inactivation during the acquisition of pluripotency is accompanied by repression of Xist, the trigger of X-inactivation, and by upregulation of its antisense counterpart, Tsix. In undifferentiated embryonic stem cells (ESCs), key transcription factors that support pluripotency repress Xist transcription. These authors show that upregulation of Tsix in ESCs depends on a different subset of pluripotency factors. Therefore, two distinct ESC-specific complexes couple reprogramming of X-inactivation to pluripotency.

The first crystal structure for an arenavirus nucleoprotein is solved, revealing some new functions. The C-terminal domain has 3′ to 5′ exonuclease activity, and it is confirmed that Lassa virus nucleoprotein is capable of cleaving short RNAs and suppressing virus-induced interferon induction. The N-terminal domain contains a unique cap-binding feature, which has implications for understanding the distinctive cap-snatching mechanism of arenaviruses.

The deformation style at moderately active volcanoes — such as Eyjafjallajökull, Iceland, which underwent an explosive summit eruption earlier this year — is little understood. These authors show that deformation associated with the eruptions at Eyjafjallajökull was unusual as it did not relate to pressure changes within a single magma chamber, and infer that this behaviour might be attributed to its off-rift setting with a 'cold' subsurface structure and limited magma at shallow depth.

Quantum networks are being developed for computation, communication and simulation. These authors demonstrate a quantum network capable of storing and reading out entanglement among multiple parties. It comprises four atomic memories connected by photonic channels, representing a significant increase in complexity in comparison with previous two-party networks.

Antihydrogen, the bound state of an antiproton and a positron, has been produced at low energies at CERN since 2002. It is of fundamental interest for testing the standard model of elementary particles and interactions. However, experiments so far have produced antihydrogen that is not confined, precluding detailed study of its structure. Here, trapping of antihydrogen atoms is demonstrated, opening the door to precision measurements on anti atoms.