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Cryo-electron microscopy is used to visualize the AMPA receptor GluA2 and the kainate receptor GluK2 in several functional states — having access to so many different structural states has enabled the authors to propose a molecular model for the gating cycle of glutamate receptors.
The first X-ray crystal structure of the mouse serotonin 5-HT3 receptor, a pentameric ligand-gated ion channel, is similar to those of other Cys-loop receptors — though here electron density for part of the cytoplasmic domain, which is important for trafficking, synaptic localization, and modulation by cytoplasmic proteins, but not visible in previous structures, is also described.
Gradual changes that occur to mammalian tooth morphology across evolutionary time were modelled in vitro and in vivo by modulation of signalling pathways in the mouse, and computer modelling was used to provide further analysis of the parameters influencing tooth morphology.
To investigate the role of sub-clonal tumour heterogeneity in cancer progression, a mouse xenograft model was used which revealed that tumour growth can be driven by a minor cell subpopulation by a non-cell-autonomous mechanism, although this minor subpopulation can be outcompeted by faster proliferating competitors.
To investigate genomic diversity within tumours, a new type of whole-genome and exome single cell sequencing has been developed using G2/M nuclei; the technique was used to sequence single nuclei from an oestrogen-positive breast cancer and a triple-negative ductal carcinoma—aneuploidy rearrangements emerged as early events in tumour formation and then point mutations evolved gradually over time.
The translation of many messenger RNAs that encode important oncogenes and transcription factors depends on the eIF4A RNA helicase to resolve G-quadruplex structures, implying eIF4A inhibition as an effective cancer therapy.
The Cancer Genome Atlas reports on molecular evaluation of 295 primary gastric adenocarcinomas and proposes a new classification of gastric cancers into 4 subtypes, which should help with clinical assessment and trials of targeted therapies.
Schizophrenia is a highly heritable genetic disorder, however, identification of specific genetic risk variants has proven difficult because of its complex polygenic nature—a large multi-stage genome-wide association study identifies 128 independent associations in over 100 loci (83 of which are new); key findings include identification of genes involved in glutamergic neurotransmission and support for a link between the immune system and schizophrenia.
Net primary production is affected by temperature and precipitation, but whether this is a direct kinetic effect on plant metabolism or an indirect ecological effect mediated by changes in plant age, plant biomass or growing season length is unclear — this study develops metabolic scaling theory to be able to answer this question and applies it to a global data set of plant productivity, concluding that it is indirect effects that explain the influence of climate on productivity, which is characterized by a common scaling relationship across climate gradients.
The anaphase-promoting complex/cyclosome (APC/C) is a large E3 ligase that mediates ubiquitin-dependent proteolysis of cell cycle regulatory proteins; here the complete secondary structure architecture of human APC/C complexed with its coactivator CDH1 and substrate HSL1 is determined at 7.4 Å resolution, revealing allosteric changes induced by the coactivator that enhance affinity for UBCH10–ubiqutin.
Proteome analysis of The Cancer Genome Atlas (TCGA) colorectal cancer specimens reveals that DNA- or RNA-level measurements cannot reliably predict protein abundance, colorectal tumours can be separated into distinct proteotypes, and that copy number alterations drive mRNA abundance changes but few extend to protein-level changes.
Mutations that dysregulate Notch1 and Ras/PI3K signalling are common in T-cell acute lymphoblastic leukaemia; here, treatment with a PI3K inhibitor is shown to induce drug resistance that is associated with downregulation of activated Notch1 signalling, suggesting that inhibition of both Notch1 and PI3K could promote drug resistance.
The crystal structures of thalidomide and its derivatives bound to the E3 ligase subcomplex DDB1–CRBN are shown; these drugs are found to have dual functions, interfering with the binding of certain cellular substrates to the E3 ligase but promoting the binding of others, thereby modulating the degradation of cellular proteins.
The COP9 signalosome (CSN) complex regulates cullin–RING E3 ubiquitin ligases—the largest class of ubiquitin ligase enzymes, which are involved in a multitude of regulatory processes; here, the crystal structure of the entire human CSN holoenzyme is presented.
Initial exposure to lipopolysaccharide (LPS) induces endotoxin tolerance, which reduces immunological reactions to LPS; here it is shown that primary LPS challenge is controlled by AhR, TDO2 and IL-10, whereas sustained effects require AhR, IDO1 and TGF-β, allowing for disease tolerance with reduced immunopathology in infections.
Programmed −1 ribosomal frameshifting (−1 PRF) is a process by which a signal in a messenger RNA causes a translating ribosome to shift by one nucleotide, thus changing the reading frame; here −1 PRF in the mRNA for the co-receptor for HIV-1, CCR5, is stimulated by two microRNAs and leads to degradation of the transcript by nonsense-mediated decay and at least one other decay pathway.
An integrated transcriptome, genome, methylome and proteome analysis of over 200 lung adenocarcinomas reveals high rates of somatic mutations, 18 statistically significantly mutated genes including RIT1 and MGA, splicing changes, and alterations in MAPK and PI(3)K pathway activity.
The exosome complex contains two catalytic subunits which degrade RNA in either a distributive (Rrp6) or a processive (Rrp44) manner—previous structures indicated how RNA could be directed to Rrp44, but the path taken to Rrp6 was unclear; here the location of the Rrp6 catalytic domain and the RNA 3′ end are determined and it is found that the RNA lies in an opposite orientation from that of the Rrp44-containing exosome structure, suggesting that the fate of an RNA may be influenced by the manner in which cofactors present it.
