Articles in 2010

Enzymes that move along DNA, such as DNA and RNA polymerases, cause the DNA ahead of them to become supercoiled. This would lead to the DNA becoming overwound, were the stress not relieved by topoisomerases. Topoisomerase inhibitors have been used as antibacterial and anticancer drugs, but the structural basis for their activity has been unclear. Here, the crystal structures are presented of a topoisomerase on DNA, either alone or in the presence of a new type of antibiotic.

The quantum Hall effect takes place in a two-dimensional electron gas under a strong magnetic field and involves current flow along the edges of the sample. In the fractional regime, counter-propagating modes that carry energy but not charge — the so-called neutral modes — have been predicted but never observed. These authors report the first direct observation of these elusive modes.

Using historical data combined with more recent satellite observations, these authors show that global phytoplankton biomass has been declining during the past century.

The appropriate initiation and termination of behavioural action sequences is imperative, but the neural mechanisms underlying the learning and execution of fixed behavioural patterns are poorly understood. Here the authors reveal start/stop neuronal activity in basal ganglia circuits that emerge during task training in mice. Genetically altering these circuits disrupted the activity and impaired performance, providing evidence for a causal relationship between the specific neuronal activity and task learning.

PPARγ ligands are used to control diabetes, but their anti-diabetic actions are puzzling. Here the authors show that phosphorylation of PPARγ by cyclin-dependent kinase 5 (Cdk5) in mice is linked to obesity induced by high-fat feeding, and that inhibition of the effect in humans by the drug rosiglitazone is closely associated with its anti-diabetic effects. Several anti-diabetic PPARγ ligands directly inhibit the effect, and thus support a more normal non-diabetic pattern of gene expression.

Pluripotent stem cells can be generated in the laboratory through somatic cell nuclear transfer (generating nuclear transfer embryonic stem cells, ntESCs) or transcription-factor-based reprogramming (producing induced pluripotent stem cells, iPSCs). These methods reset the methylation signature of the genome — but to what extent? Here it is found that mouse iPSCs 'remember' the methylation status of their tissue of origin, but the methylation of ntESCs is more similar to that of naturally produced ES cells.

During protein synthesis within the ribosome, transfer RNAs (tRNAs) move sequentially through different sites as their attached amino acids are transferred onto the growing protein chain. Large conformational movements accompany this process. Here, a staggering 1.9 million electron cryomicroscopy images of the ribosome have been processed to visualize these changes. The results reveal that the ribosome functions as a Brownian machine that couples spontaneous changes driven by thermal energy to directed movement.

The microbial content of the human gut has been the focus of much research interest recently. Now another layer of complexity has been added: the viral content of the gut. Virus-like particles were isolated from faecal samples from four sets of identical twins and their mothers, at three time points over a one-year period. The viromes (metagenomes) of these particles were then sequenced. The results show that there is high interpersonal variation in viromes, but that intrapersonal diversity was very low over this time period.

K⁺ channels can convert between conductive and non-conductive forms through mechanisms that range from flicker transitions (which occur in microseconds) to C-type inactivation (which occurs on millisecond to second timescales). Here, the crystal structures are presented of the potassium channel KcsA in an open-inactivated conformation and 'trapped' in several partially open conformations. The structures indicate a molecular basis for C-type inactivation in K⁺ channels.

Extended cocaine taking triggers several structural and functional changes in the brain that may lead to compulsive drug seeking, but the mechanisms that regulate the process are unclear. Here, a microRNA — miR-212 — is identified that is upregulated in the striatum of rats with a history of extended access to cocaine. The authors suggest that miR-212 protects against the development of compulsive drug taking, and that it may act through the CREB protein, a known regulator of the rewarding effects of cocaine.

Cardiac hypertrophy is associated with a decrease in expression of the adult isoform of the molecular motor myosin heavy chain (α-MHC) and the induction of expression of its fetal isoform (β-MHC). Here the authors reveal the mechanism regulating this switch in expression, which impairs heart function. Cardiac stress in adult hearts reactivates the developmental chromatin-modifying complex Brg1/BAF, which interacts with histone deacetylase and poly (ADP ribose) polymerase to induce a pathological α-MHC-to-β-MHC shift.

With the start-up of the first X-ray free-electron laser, a new era has begun in dynamical studies of atoms. Here the facility is used to study the fundamental nature of the electronic response in free neon atoms. During a single X-ray pulse, they sequentially eject all their ten electrons to produce fully stripped neon. The authors explain this electron-stripping in a straightforward model, auguring favourably for further studies of interactions of X-rays with more complex systems.

The backbones of all natural peptides and proteins are composed of amide bonds. In the laboratory, the construction of such bonds generally relies on dehydrative approaches, although there are alternatives. It is now shown that the activation of amines and nitroalkanes with an electrophilic iodine source can lead directly to amide products.

Ultraviolet radiation causes damage to DNA in skin cells, blocking DNA replication and causing mutations that can lead to cancer. One way in which the cell deals with such damage involves specialized DNA polymerases, such as Polη, that can bypass lesions. Here the crystal structure is presented of Pol? in complex with a thymine–thymine dimer and with undamaged DNA. The bulky thymine dimer is accommodated in an atypically large active site, and stabilized by interactions not found in other polymerases.

Ultraviolet radiation causes damage to DNA in skin cells, blocking DNA replication and causing mutations that can lead to cancer. One way in which the cell deals with such damage involves specialized DNA polymerases, such as Polη, that can bypass lesions. Here the crystal structure of Polη is presented at four consecutive steps during DNA synthesis through thymine dimers. Polη acts like a 'molecular splint' to stabilize damaged DNA, and accommodates the thymine dimer in an atypically large active site.

The canonical role of messenger RNA (mRNA) is in protein coding and synthesis. But could mRNAs also have a role that is related to their ability to compete for microRNA binding? Here, the functional relationship between the mRNAs produced by the PTEN tumour suppressor gene and its pseudogene PTENP1 is investigated. The results suggest that pseudogenes have a biological function, in sequestering microRNAs and so affecting their regulation of gene expression.

In bacteria, the lack of compartmentalization within membrane-enclosed compartments has made it difficult to determine how mature messenger RNAs are spatially distributed. Here the authors use fluorescence experiments in bacteria to follow mRNA dispersal after transcription. They find, surprisingly, that the newly transcribed mRNAs show limited diffusion, and speculate that the packed chromosomal material may itself act as a partition to separate translation from mRNA degradation.

Autophagy is a cellular process by which proteins and organelles are sequestered in autophagosomal vesicles and delivered to the lysosome for degradation. Here the authors present a proteomic analysis of the autophagy interaction network in human cells. Their results reveal a network of signalling modules and extensive connectivity among subnetworks. This global view of the mammalian autophagy pathway will be an important resource for future mechanistic understanding of this pathway.

Translation elongation factor 2 (EF2) from archaea and eukaryotes contains a unique, post-translationally modified histidine residue called diphthamide, which is the target of diphtheria toxin. The biosynthesis of diphthamide involves three steps; here it is shown that the first step in the archaeon Pyrococcus horikoshii requires an unusual iron–sulphur-cluster enzyme, Dph2. It catalyses unprecedented chemistry.

Here the 2.1 Å crystal structure of human immunodeficiency virus (HIV) Tat protein complexed with the positive transcription elongation factor P-TEFb is reported. This shows that Tat binding changes the structure of P-TEFb, which may suggest opportunities for developing inhibitors that block only the form of P-TEFb used by the virus.