Articles in 2015

The cryo-electron microscopy structure of the eukaryotic initiation factor 3 (eIF3) within the larger 43S complex is determined; the improved resolution enables visualization of the secondary structures of the subunits, as well as the contacts between eIF3 and both eIF2 and DHX29.

A ChIP-seq analysis of the DNA-binding properties of mutant gain-of-function p53 protein compared to wild-type p53 reveals the gain-of-function proteins bind to and activate a distinct set of genes including chromatin modifying enzymes such as the histone methyltransferase MLL; small molecular inhibitors of MLL function may represent a new target for cancers with mutant p53.

Ground-sourced tree density data is assembled to provide a global map of tree density, which reveals that there are three trillion trees (tenfold more than previous estimates); tree numbers have declined by nearly half since the start of human civilization and over 15 billion trees are lost on an annual basis.

This study describes a new model of eukaryotic replication termination in which converging leading strands pass each other unhindered and the replicative DNA helicase is unloaded late, after all strands have been ligated.

A candidate-based genetic screen in Drosophila expressing 30 G₄C₂-repeat-containing RNAs finds that RanGAP, a key regulator of nucleocytoplasmic transport, is a potent suppressor of neurodegeneration; the defects caused by the G₄C₂ repeat expansions can be rescued with antisense oligonucleotides or small molecules targeting the G-quadruplexes.

Eukaryotes acquired their prokaryotic genes in two episodes of evolutionary influx corresponding to the origin of mitochondria and plastids, respectively, followed by extensive differential gene loss, uncovering a massive imprint of endosymbiosis in the nuclear genomes of complex cells.

The atomic structure of human γ-secretase at 3.4 Å resolution, determined by single-particle cryo-electron microscopy.

The first crystal structures of complexes between synaptotagmin-1 and neuronal SNARE, bound to either Ca²⁺ or Mg²⁺, are described, and show that Ca²⁺-triggered neurotransmitter release relies on a large, Ca²⁺-independent interface.

The crystal structure of the 240-kilodalton C–P lyase core complex from the bacterium E. coli offers insights into the relatively unknown mechanisms of the enzymatic machinery that allows some microbes to extract phosphate from phosphonate compounds.

The X-ray crystal structure of the ABC transporter PglK, which facilitates the flipping of lipid-linked oligosaccharides (LLOs) in C. jejuni, in inward- and outward-facing states is solved; the structures and follow-up biochemical experiments support an unprecedented mechanism in which the polyprenyl tail of LLO remains partially embedded in the lipid bilayer, and the pyrophosphate-oligosaccharide head group is flipped into the outward-facing cavity after ATP is hydrolysed.

The PINK1 ubiquitin kinase is shown to recruit the two autophagy receptors NDP52 and OPTN to mitochondria to activate mitophagy directly, independently of the ubiquitin ligase parkin; once recruited to mitochondria, NDP52 and OPTN recruit autophagy initiation components, and parkin may amplify the phospho-ubiquitin signal generated by PINK1, resulting in robust autophagy induction.

X-ray crystallography and molecular dynamics simulations of the μ-opioid receptor reveal the conformational changes in the extracellular and intracellular domains of this G-protein-coupled receptor that are associated with its activation.

In the uninjured liver, a population of self-renewing, diploid hepatocytes is identified near the central vein; these cells respond to Wnt signals that are provided by the adjacent central vein endothelial cells, and can give rise to all other hepatocytes to maintain liver homeostasis.

This study describes the long-awaited crystal structures for hypoxia-inducible factor (HIF) heterodimers, including complexes bound to small molecules and DNA; the HIF–ARNT architecture is distinct from the bHLH-PAS-containing CLOCK–BMAL1 heterodimer, and HIF mutations linked to cancer can be mapped to important structural regions, with the structures providing future reference for small-molecule drug discovery efforts.

The molecular basis of multidrug tolerance in chronic urinary tract infections is mediated by mutations in the N-subdomain-1 of the Escherichia coli HipA protein kinase.

Solving the crystal structure of an exosome complex from yeast, bound to different RNA substrates, offers insights into how the exosome can be utilized for precise processing of some 3′ ends, such as that of the 5.8S rRNA, while other RNAs are degraded to completion.

Cryo-electron microscopy is used to visualize the double hexamer of the eukaryotic minichromosome maintenance complex (MCM), which is assembled during the G1 phase of DNA replication; two interdigitated hexamers have a central channel that tightly fits a DNA duplex, and the orientation of the tilted single hexamers sheds light on many functional aspects, particularly in the initial origin DNA melting.

Gram-positive bacteria use peptidase-containing ATP-binding cassette transporters (PCATs) to export quorum-sensing and antimicrobial polypeptides; here, the X-ray crystal structures of PCAT1 from Clostridium thermocellum in the absence and presence of ATP are reported.

Genomic approaches in more than 500 patients are used to extend the number of chronic lymphocytic leukaemia (CLL) driver alterations, and also identify novel recurrent mutations in non-coding regions, including an enhancer of PAX5 and the 3′ untranslated region of NOTCH1, which lead to aberrant splicing events, increased NOTCH1 protein stability and activity, and an adverse clinical outcome.

The assembly, architecture and role of the bacterial type VI secretion system (T6SS) membrane core complex is presented.