Protein model discrimination using mutational sensitivity derived from deep sequencing

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Highlights? Individual mutant phenotypes in a saturation library derived via deep sequencing ? Residue depth and active-site residue derivation from mutant phenotypes ? Mutant-phenotype-derived parameters used for protein model discrimination ? Derivation of sequence-structure-function relationships without protein isolation     

A DNA-Damage Selective Role for BRCA1 E3 Ligase in Claspin Ubiquitylation,CHK1 Activation,and DNA Repair

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Highlights? BRCA1 E3 ligase activity is essential for a subset of DNA damage responses ? BRCA1 V26A mutant cells are sensitive to topoisomerase inhibitors but not mitomycin C ? BRCA1 selectively ubiquitylates claspin after topoisomerase inhibition ? BRCA1 E3 ligase inactivation selectively impairs CHK1 activation     

Crystal structures of Aureochrome1 LOV suggest new design strategies for optogenetics

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Highlights? Crystal structures in dark and light states determined for Aureochrome1 LOV ? Significant light induced change observed in F298 and quaternary structure ? Potential photocycle mutant variants, altering the light-state lifetime, identified ? Possible mechanism of signaling in topologically unique Aureo1 speculated     

AMPK Is a Negative Regulator of the Warburg Effect and Suppresses Tumor Growth In Vivo

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Highlights? Loss of AMPKα1 cooperates with the Myc oncogene to accelerate lymphomagenesis ? AMPKα dysfunction enhances aerobic glycolysis (Warburg effect) ? Inhibiting HIF-1α reverses the metabolic effects of AMPKα loss ? HIF-1α mediates the growth advantage of tumors with reduced AMPK signaling     

Distinct Metabolic Flow Enables Large-Scale Purification of Mouse and Human Pluripotent Stem Cell-Derived Cardiomyocytes

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Highlights? Integrated “omic” analyses reveal metabolic hallmarks in ESCs and cardiomyocytes ? Glucose depletion and lactate supplementation can purify PSC-derived cardiomyocytes ? Cardiomyocytes can use lactate efficiently for energy metabolism ? Transplanted purified human ESC-derived cardiomyocytes do not form tumors     

β1 Integrin Establishes Endothelial Cell Polarity and Arteriolar Lumen Formation via a Par3-Dependent Mechanism

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Highlights? β1 integrin deletion results in loss of endothelial polarity and vessel patency ? β1 integrin regulates cell-cell adhesion protein distribution in the endothelium ? Polarity loss is typified by decreased Par3 expression ? Par3 can partially rescue lumen formation in the β1 integrin mutant     

The structural basis for tight control of PP2A methylation and function by LCMT-1

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Highlights? LCMT-1 makes extensive contacts to PP2A active site for methylation of PP2A tail ? PP2A methylation is stimulated by phosphatase activation, hampered by inactivation ? LCMT-1 would facilitate efficient transition of activated PP2A to holoenzymes ? A high-affinity dnLCMT-1 mutant attenuates the cell cycle without causing cell death     

In Vivo HIF-Mediated Reductive Carboxylation Is Regulated by Citrate Levels and Sensitizes VHL-Deficient Cells to Glutamine Deprivation

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Highlights? HIF is necessary and sufficient to induce reductive carboxylation in RCC cell lines ? HIF promotes the reductive carboxylation flux by reducing citrate levels ? HIF-expressing tumors display reductive carboxylation in vivo ? HIF renders RCC cells sensitive to glutaminase inhibition in vitro and in vivo     

The structure of dimeric apolipoprotein A-IV and its mechanism of self-association

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Highlights? Structure of dimeric apoA-IV solved to 2.4 Å by X-ray crystallography ? Structure confirmed through biochemical and mutational analysis ? Understanding of apoA-IV dimerization allowed us to create a monomeric mutant ? Structural features in the dimer offer clues to the genesis of apoA-IV lipoproteins     

Endogenous Purification Reveals GREB1 as a Key Estrogen Receptor Regulatory Factor

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Highlights? A proteomic method identifies protein-protein interaction in primary tumors ? GREB1 is the top estrogen-induced ER-interacting protein ? GREB1 is an essential ER cofactor recruited to chromatin ? GREB1 is an independent prognostic marker     

Patient-Specific Orthotopic Glioblastoma Xenograft Models Recapitulate the Histopathology and Biology of Human Glioblastomas In Situ

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Highlights? Orthotopic xenograft models were established by primarily cultured GBM cells ? These models recapitulate pathological and genomic properties of parental tumors ? Treatment response of parental tumors was reproduced in the animal models ? signatures associated with GBM clinical aggressiveness were identified     

Deep Brain Photoreceptors Control Light-Seeking Behavior in Zebrafish Larvae

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Highlights? Larvae aggregate in the light even after loss of retinal and pineal photoreception ? Dark-driven photokinesis is absent in eyeless otpa mutant larvae ? The melanopsin opn4a is coexpressed with otpa and selectively lost in otp mutants ? otpa neurons of the preoptic area are deep brain photoreceptors for dark photokinesis     

SIP1 Mediates Cell-Fate Decisions between Neuroectoderm and Mesendoderm in Human Pluripotent Stem Cells

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Highlights? Smad-interacting protein 1 (SIP1) regulates hESC differentiation ? SIP1 upregulation promotes neuroectodermal differentiation ? SIP1 inhibits mesendodermal and endodermal differentiation ? SMAD2/3 and NANOG/OCT4/SOX2 cooperatively regulate SIP1 expression     

Keeping cell identity in Arabidopsis requires PRC1 RING-finger homologs that catalyze H2A monoubiquitination

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Highlights? AtBMI1A/B proteins prevent misexpression of embryonic traits in somatic cells ? PRC2 and AtBMI1A/B proteins maintain cells in their differentiated state ? AtBMI1A/B proteins mediate H2A monoubiquitination     

Perivascular Nitric Oxide Activates Notch Signaling and Promotes Stem-like Character in PDGF-Induced Glioma Cells

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Highlights? Perivascular niche nitric oxide activates Notch in PDGF-induced gliomas ? Notch signaling drives tumor stem-like characteristics and reduces survival ? Loss of eNOS activity decreases tumor stem-like characteristics ? Suppressing eNOS activity prolongs survival in glioma-bearing mice     

Comprehensive Analysis of Silencing Mutants Reveals Complex Regulation of the Arabidopsis Methylome

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Highlights? Genome-wide single-nucleotide resolution methylation maps in 86 silencing mutants ? Complex interplays between different DNA methylation pathways ? Identification of novel regulators of DNA methylation     

The Centrosome Regulates the Rab11- Dependent Recycling Endosome Pathway at Appendages of the Mother Centriole

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Highlights? Endosome-proteins localize to centrosomes independent of membranes ? Rab11 and its modulators localize to mother centriole appendages ? Mother centriole appendages regulate membrane recycling through Rab11     

Visualizing the Determinants of Viral RNA Recognition by Innate Immune Sensor RIG-I

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Highlights? Crystallographic structure of RIG-I with 5′ triphosphorylated RNA duplex and ADP ? Solution biophysical analysis of ATP-dependent RIG-I conformational change ? The structural basis for ATP-stimulated RIG-I activation