Protein Quality Control Acts on Folding Intermediates to Shape the Effects of Mutations on Organismal Fitness

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Highlights? Proteases (Lon) and chaperonins (GroEL/ES) act on folding intermediates ? Fitness effects of Lon knockout and GroEL/ES overexpression are correlated ? Stability-changing mutations affect the total abundance of a protein in cytoplasm ? A dynamic model predicts fitness effects of mutations and orthologous replacements     

Zinc Drives a Tertiary Fold in the Prion Protein with Familial Disease Mutation Sites at the Interface

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Highlights? Zinc binds to the prion protein octarepeat domain ? The zinc-bound octarepeat makes a tertiary contact to C-terminal helices 2 and 3 ? The encompassed surface carries a majority of the mutations in familial prion disease ? Familial mutations weaken this zinc-driven tertiary contact     

Genome sequencing of pediatric medulloblastoma links catastrophic DNA rearrangements with TP53 mutations

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Highlights? Complex chromosomal alterations (chromothripsis) observed in medulloblastomas ? Cancers with such alterations harbor TP53 mutations ? Context-specific link between the status of p53 and likelihood of chromothripsis ? p53 status and chromothripsis also correlate with aggressive acute myeloid leukemia     

Structural and Functional Integration of the PLCγ Interaction Domains Critical for Regulatory Mechanisms and Signaling Deregulation

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Highlights? Domains from PLCγ regulatory region show structural and functional integration ? Only cSH2 domain interacts with the PLC-core forming a high affinity surface ? Activation involves removal of autoinhibition and dissociation from the receptor ? Disease-linked mutations map to the autoinhibitory interface     

Structure of NPP1, an Ectonucleotide Pyrophosphatase/Phosphodiesterase Involved in Tissue Calcification

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Highlights? We determine the crystal structure of mouse NPP1 ? We elucidate the mechanism of NPP1 dimer formation and secretion ? The structure explains the dramatic functional differences between NPP1 and NPP2 ? The structure allows defining the impact of pathogenic mutations in human NPP1     

A Role for Intersubunit Interactions in Maintaining SAGA Deubiquitinating Module Structure and Activity

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Highlights? Structures of the SAGA deubiquitinating module lacking the Sgf11 zinc finger domain ? The DUB module lacking the Sgf11 zinc finger forms a domain swapped complex dimer ? The conformational changes accompanying domain-swapping disrupt the active site ? Activating mutations in Ubp8 promote the compact form of the DUB module     

Mutational tipping points for switching protein folds and functions

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Highlights? Switching between 3α and 4β+α folds can occur in multiple ways ? Single-residue mutations at diverse positions can induce fold switching ? Mutations lead to a near-complete shift in equilibrium between the two folds ? New function can be gained before the relevant fold is significantly populated     

Disease mutations in the ryanodine receptor central region: crystal structures of a phosphorylation hot spot domain

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Highlights? Crystal structures of a central RyR domain contain phosphorylation sites ? Eleven RyR1 disease mutations cluster on two opposite faces of the domain ? The RyR1 L2867G mutation causes a drastic destabilization ? In vitro phosphorylation identifies 5 PKA and 4 CaMKII targets     

Folding and Self-Assembly of the TatA Translocation Pore Based on a Charge Zipper Mechanism

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Highlights? Charge zippers as a new concept for folding and assembly of membrane proteins ? 3D structure of TatA pore explains translocation of folded proteins across membrane ? Ladders of salt bridges connect an amphiphilic palisade that can span the bilayer ? MD simulations and specific charge mutations support the charge zipper model     

Structure of the Catalytic Region of DNA Ligase IV in Complex with an Artemis Fragment Sheds Light on Double-Strand Break Repair

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Highlights? The crystal structure of the DNA ligase IV/Artemis complex was solved at 2.4 Å ? The structure of DNA ligase IV (residues 1–609) shows inserts ? An Artemis helix forms a three-helix bundle with two helices from DNA ligase IV ? The structure provides insights into the mutations causing LIG4 syndrome     

A Genome-wide RNAi Screen Reveals a Trio-Regulated Rho GTPase Circuitry Transducing Mitogenic Signals Initiated by G Protein-Coupled Receptors

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Highlights? Human cancers harbor frequent mutations in Gq-linked GPCRs and Gα_q subunits ? A genome-wide RNAi screen revealed that Trio is essential for activating AP-1 via Gα_q ? A network of Trio-regulated Rho GTPases and MAPKs links Gq to the nucleus ? A hard-wired Gq-Trio signaling axis promotes the growth of many human malignancies     

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     

Spatial Restriction of FGF Signaling by a Matrix Metalloprotease Controls Branching Morphogenesis

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Highlights? Drosophila Matrix Metalloprotease (Mmp) inhibits FGF signaling ? An FGF – MMP feedback loop regulates branching morphogenesis ? Mmp2 spatially regulates FGF signaling in epithelia     

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     

Uncovering a Region of Heat Shock Protein 90 Important for Client Binding in E. coli and Chaperone Function in Yeast

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Highlights? Using a genetic screen, we selected for defective mutants of E. coli Hsp90 ? The mutants are impaired in ATP-dependent chaperone activity ? The mutations define a client-binding region of E. coli Hsp90 ? Mutation of homologous residues in yeast Hsp90 causes in vivo and in vitro defects     

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     

Evidence for Geomagnetic Imprinting as a Homing Mechanism in Pacific Salmon

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Highlights? Sockeye salmon use geomagnetic imprinting as a homing mechanism ? The homing route of salmon is predicted by magnetic field drift (secular variation)     

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