Articles in 2014

An X-ray structure is presented for metabotropic glutamate receptor 5, a class C G-protein-coupled glutamate receptor linked to fragile X syndrome and neurological disorders; this study provides insights into the protein’s mechanism of action.

This study describes the conversion of human fetal and adult vascular endothelial cells into engraftable haematopoietic progenitors by transduction with some transcription factors and then culture on a vascular niche feeder layer; the haematopoietic progenitors may be useful for the generation of engraftable healthy and long-lasting haematopoietic cells for treatment of inherited and acquired blood disorders.

Genome-wide analysis of matched human IVF embryonic stem cells (IVF ES cells), induced pluripotent stem cells (iPS cells) and nuclear transfer ES cells (NT ES cells) derived by somatic cell nuclear transfer (SCNT) reveals that human somatic cells can be faithfully reprogrammed to pluripotency by SCNT; NT ES cells and iPS cells derived from the same somatic cells contain comparable numbers of de novo copy number variations, but whereas DNA methylation and transcriptome profiles of NT ES cells and IVF ES cells are similar, iPS cells have residual patterns typical of parental somatic cells.

The three-dimensional structure of intact human γ-secretase complex at 4.5 Å resolution is revealed by cryo-electron-microscopy single-particle analysis; the complex comprises a horseshoe-shaped transmembrane domain containing 19 transmembrane segments, and a large extracellular domain from nicastrin, which sits immediately above the hollow space formed by the horseshoe.

Future rounds of nuclear arms control would ideally involve direct inspection of nuclear warheads using procedures that give inspectors high confidence about the authenticity of submitted nuclear items yet give no information about their design; this is now shown to be achievable using zero-knowledge protocols in neutron imaging of nuclear warheads.

Metastatic cancer cells are shown to have a tendency towards forming a bulky glycocalyx owing to the production of large glycoproteins, and this cancer-associated glycocalyx has a mechanical effect on the spatial organization of integrins — by funnelling integrins into adhesions, integrin clustering and signalling is promoted, which leads to enhanced cell survival and proliferation.

The emergence of Gram-negative pathogens resistant to carbapenem antibiotics is a global health concern and carbapenem resistance often arises through acquisition of β-lactamase enzymes; this study identifies the natural fungal product aspergillomarasmine A as a metallo-β-lactamase inhibitor and a potential treatment to tackle carbapenem resistance.

X-ray crystal structures are presented of the N-methyl-d-aspartate (NMDA) receptor, a calcium-permeable ion channel that opens upon binding of glutamate and glycine; glutamate is a key excitatory neurotransmitter and enhanced structural insight of this receptor may aid development of therapeutic small molecules.

Focusing on two ill-characterized subtypes of medulloblastoma (group 3 and group 4), this study identifies prevalent genomic structural variants that are restricted to these two subtypes and independently bring together coding regions of GFI1 family proto-oncogenes with active enhancer elements, leading to their mutually exclusive oncogenic activation.

Lipopolysaccharide, an essential component of the outer membranes of Gram-negative bacteria, is inserted by LptD–LptE, a protein complex with a unique ‘barrel and plug’ architecture; the structure, molecular dynamics simulations and functional assays of the LptD–LptE complex of Salmonella typhimurium suggest that lipopolysaccharide may pass through the barrel and is then inserted into the outer leaflet of the outer membrane through a lateral opening between two β-strands of LptD.

The basic five-digit limb of tetrapods has been altered many times during evolution, usually by the progressive loss of digits — this study tracks the molecular underpinnings of this change, showing that in comparison to mouse, the polarized gene expression in the bovine limb bud is progressively lost due to evolutionary alteration of the cis-regulatory sequences that control Ptch1 expression in response to SHH signalling in the digit-forming handplate.

A study of limb development in multiple mammals reveals that evolutionary digit loss has occured in many different ways—at different stages and by different mechanisms, such as regulation of Shh in initial digit specification events or by removal of digits through cell death.

Polyketide synthases are multidomain enzymes that produce polyketides, which form the basis of many therapeutic agents; here, electron cryo-microscopy is used to establish the structure of a bacterial full-length module, and to elucidate the structural basis of both intramodule and intermodule substrate transfer.

Quantum computing promises advantages over classical computing for certain problems; now ‘quantum contextuality’ — a generalization of the concept of quantum non-locality — is shown to be a critical resource that gives the most promising class of quantum computers their power.

Large-scale single-cell RNA-seq of stimulated primary mouse bone-marrow-derived dendritic cells highlights positive and negative intercellular signalling pathways that promote and restrain cellular variation.

The Eucalyptus grandis genome has been sequenced, revealing the greatest number of tandem duplications of any plant genome sequenced so far, and the highest diversity of genes for specialized metabolites that act as chemical defence and provide unique pharmaceutical oils; genome sequencing of the sister species E. globulus and a set of inbred E. grandis tree genomes reveals dynamic genome evolution and hotspots of inbreeding depression.

X-ray crystal structures of a tRNA synthetase bound to wild-type and mutant alanine tRNAs reveal the structural basis for selectivity.

GABA_A receptors are the principal mediators of rapid inhibitor synaptic transmission in the brain, and a decline in GABA_A signalling leads to diseases including epilepsy, insomnia, anxiety and autism; here, the first X-ray crystal structure of a human GABA_A receptor, the human β3 homopentamer, reveals structural features unique for this receptor class and uncovers the locations of key disease-causing mutations.

Traits responsible for recent niche divergence between sympatric threespine stickleback species are subjected to forward genetic analysis; additive variation at several loci across the genome accounts for most of the genetic basis of ecological divergence, with a further role for epistatic interactions that disadvantage hybrids.

Damaged mitochondria are removed by mitophagy, and defects in mitophagy are linked to Parkinson’s disease; here it is shown that USP30, a deubiquitinase localized to mitochondria, antagonizes mitophagy by removing the ubiquitin tags put in place by Parkin, USP30 inhibition is therefore potentially beneficial for Parkinson’s disease by promoting mitochondrial clearance and quality control.