Articles in 2009

In 1966, Frank Westheimer proposed that the large shift in the pK_a of a key lysine residue (Lys 115) in the active site of the enzyme acetoacetate decarboxylase was because of the neighbouring charge of another lysine reside (Lys 116); this is said to be a classic example of enzymatic 'microenvironment effects'. Here, the X-ray crystal structure of acetoacetate decarboxylase is solved, revealing that the shift in pK_a cannot be due to Lys 116 but is instead due to the presence of a long hydrophobic funnel near Lys 115.

Eukaryotic cells contain membrane-bound organelles that can undergo fusion with each other in a regulated manner; this is thought to be mediated by SNAREs (soluble N-ethylmaleimide-sensitive factor attachment protein receptors). Here, the complete reconstitution of endosome fusion using Rab5 and SNARE proteins highlights the functional relationship between these two machineries.

Theta oscillations are essential to temporal encoding in the hippocampus; they clock hippocampal activity during awake behaviour and rapid eye movement (REM) sleep. Although these 4–10-Hz oscillations are widely believed to be synchronized throughout the hippocampus, they are now demonstrated to form waves that travel across the hippocampal circuit, making the organization of time in the hippocampus similar to that on Earth—a progression of local time zones.

Listeria monocytogenes is responsible for severe food-borne infections. The first global comparative transcriptome analysis of this species reveals successive and coordinated global transcriptional changes during infection and points to previously unknown regulatory mechanisms in bacteria.

The differentiation of the parasite Trypanosoma brucei, the cause of sleeping sickness, from the human blood to the tsetse fly stage is known to require two signals – low temperature and citrate and/or cis-aconitate – but how these signals were perceived was unknown. The trypanosome carboxylate-transporter family PAD is now revealed to be essential in this process.

Histone acetylation has been implicated in learning and memory. Neuron-specific overexpression of histone deacetylase 2 (HDAC2), but not HDAC1, is shown to decrease memory formation in a rodent model. This encourages development and testing of HDAC2-selective inhibitors for human diseases associated with memory impairment.

Mice deficient in the Polycomb repressor Bmi1 have a shortened lifespan and develop numerous abnormalities including defects in stem cell self-renewal and thymocyte maturation. Here it is demonstrated that cells derived from Bmi1^−/− mice also show a marked elevation in the intracellular levels of reactive oxygen species, corresponding to the derepression of previously identified Polycomb target genes and sufficient to engage the DNA damage response pathway.

Although structural variation has been previously associated with autism spectrum disorders, this study reports a genome-wide significant association of common variants with susceptibility to this disorder group. The results implicate neuronal cell-adhesion molecules in the pathogenesis of this group of neurodevelopmental and neuropsychiatric disorders.

Individual odorant molecules have been shown to activate several distinct classes of olfactory neurons at once, suggesting a combinatorial code. Using a new behavioural assay and cutting-edge genetic control of specific neurons in the fruitfly, attraction to low concentrations of vinegar is now shown to rely exclusively on one or two of the six activated neuronal centres.

Cortical gamma oscillations (20–80 Hz) predict increases in focused attention, and failure in gamma regulation is a hallmark of neurological and psychiatric disease; however, what induces this activity band is unclear. Here, by using a cell-type targeted optogenetic approach, it is revealed that gamma oscillations can be driven by specific activation of fast-spiking interneurons in vivo, and that sensory input relative to these oscillations can determine the extent of evoked cortical activity.

In this manuscript, the authors develop a computational framework to design protein peptide interactions, and they use the method to identify peptides that bind to human bZIP transcription factors. Despite that fact that bZIP proteins share strong sequence and structural similarities, the authors were able to find peptides that selectively bound to one family, but not the 19 other families.

In this study, Watanabe and colleagues investigate the contribution of kinetochore geometry as a determinant for bipolar versus monopolar attachment. They find that cohesion at the core centromere induces a monopolar attachment seen in meiosis I; in contrast, cohesion at the peri-centromeric region promotes bipolar attachment in mitosis.

Knoblich and colleagues use a library of Drosophila strains expressing inducible hairpin RNA interference constructs to study the Notch signalling pathway during external sensory organ development. They assign putative loss-of-function phenotypes to 21.2% of the protein-coding Drosophila genes, identify 6 new genes involved in asymmetric cell division and 23 novel genes regulating the Notch signalling pathway.

This study has developed the first small molecule NEDD8-activating enzyme (NAE) inhibitor, which induces cancer cell death and exerts anti-tumour activity in preclinical mouse models. This work establishes NAE as an anti-cancer target and may lead to new anti-cancer therapeutics.

This paper presents the X-ray crystal structure of a gap junction channel at 3.5 Å resolution. The structure shows how human connexin 26 connexons interact, in an apparently open conformation, and provides insight into channel gating by the transjunctional voltage.

The crystal structure of CRM1 in complex with a substrate called snurportin 1 is presented. Snurportin 1 binds CRM1 in a bipartite manner by means of an amino-terminal leucine-rich nuclear export signal (LR-NES) and its nucleotide-binding domain. Further analysis reveals a second NES epitope in the nucleotide-binding domain of snurportin 1, and multipartite recognition of individually weak NES epitopes may be a common feature of CRM1 binding.

Description of a novel function for autophagy in regulating lipid metabolism, called 'macrolipophagy', in which lipid droplets and autophagic components associate during starvation and inhibition of autophagy increases lipid storage in lipid droplets. A critical role of autophagy in regulating lipid metabolism is identified, and may provide a new approach to prevent lipid accumulation in disease.

This study presents an exceptionally well-preserved fossil fish from the Silurian period (more than 418 million years ago) from southern China. The new form shows a mix of derived and primitive features. It is the earliest known well-preserved bony fish, and is a basal member of the lobe-finned fishes (which includes, today, the lungfishes, coelacanth and all land vertebrates), meaning that the split between ray-finned and lobe-finned bony fishes must have happened at least 419 million years ago, suggesting a deep history for jawed vertebrates.

In eukaryotes, many genes contain one or more introns — sequences that are transcribed into mRNA, but which are then excised before the mRNA is translated into protein. Multiprotein–RNA complexes called snRNPs are the machinery that clips these introns out. This study presents the structure of the U1 snRNP, which assembles at the 5′ end of the intron; the subunit interactions suggest a model by which the snRNP is assembled and the 5′ splice site is recognized.

This study has developed a new imaging technology to track the activation of CaMKII locally within an individual dendritic spine. CaMKII is transiently activated during synaptic potentiation and does not spread to neighbouring dendritic domains, thus ensuring that synaptic changes remain localized.