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Volume 20 Issue 5, May 2013

During early development, one of the two female X chromosomes forms a compact, silent nuclear compartment. Obuse and colleagues now provide new insights into the condensation mechanisms. Artwork by Yuka Naraki shows two calico cats, whose tortoiseshell-like color is a typical phenotype of X inactivation, representing compact inactive and decondensed active X. pp 566–573


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News & Views

  • Voltage-activated ion channels contain S1–S4 domains that endow them with exquisite voltage sensitivity. X-ray crystal structures provided a major breakthrough in elucidating the mechanistic basis of voltage sensing, revealing a helix-turn-helix motif termed the voltage-sensor paddle. A study in this issue demonstrates that this motif exists in the open state of Kv channels when embedded in native biological membranes and puts forward new ideas about its functional role in the mechanism of voltage sensing.

    • Jeet Kalia
    • Kenton J. Swartz
    News & Views
  • BAK is a proapoptotic BCL-2–family protein that resides in the mitochondrial outer membrane and transforms into a toxic oligomeric pore in response to overwhelming cellular stress. Biochemical and structural analyses of hydrocarbon-stapled signaling peptides in complex with BAK establish a direct mechanism for BAK activation.

    • Loren D. Walensky
    News & Views
  • By comparing ligand-free G protein–coupled receptor (GPCR) structures with those of receptors bound to inverse agonists, agonists and signaling effectors, two recent papers refine the understanding of GPCR activation. One group also reported the oligomeric assembly of the β1 adrenergic receptor in its ligand-free form, raising the question of the role of oligomers in receptor activation.

    • Michel Bouvier
    News & Views
  • RNA is believed to have been the first reservoir of genetic information, but despite its ancient history, RNA continues to fascinate and is only now beginning to be understood in its entire variety and communication modality. New discoveries include the pseudogene RNA network regulating PTEN transcription and translation and the identification of circular RNAs as a new class of competing endogenous RNA molecules that sequester microRNAs to suppress their function.

    • Riccardo Taulli
    • Cristian Loretelli
    • Pier Paolo Pandolfi
    News & Views
  • A recent study on the mechanism of microRNA–mediated gene silencing suggests that microRNA–induced silencing complexes inhibit ribosome scanning by recruiting the DEAD-box RNA helicase eIF4AII through an interaction with the NOT1 subunit of the CCR4–NOT deadenylase complex.

    • Elisa Izaurralde
    News & Views
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Research Highlights

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  • The mechanisms underlying gene silencing and epigenetic stability of heterochromatin are not fully understood. New studies in fission yeast now show that heterochromatin differs from euchromatin in the turnover of histones, and they identify the histone deacetylase Clr3 as a factor that inhibits histone turnover across heterochromatin domains and is crucial for the stable inheritance of heterochromatin in cis.

    • Ozan Aygün
    • Sameet Mehta
    • Shiv I S Grewal
  • Ubiquitin (Ub) monomers can form different types of chains, depending on which of its seven lysine residues are involved in the linkages. Now linkage-specific deubiquitinases are used to explore the architecture of heterotypic Ub chains, and Lys6 chains are shown to feature an asymmetric interface and a different conformation for Ub.

    • Manuela K Hospenthal
    • Stefan M V Freund
    • David Komander
  • The human inactive X chromosome (Xi) compacts into a silent nuclear compartment, called a Barr body, that is enriched in repressive histone marks. Xi compaction is now shown to require a molecular network involving the heterochromatin protein 1–binding protein HBiX1 and SMCHD1, which interact with domains enriched for trimethylated histone H3 Lys9 (H3K9me3) and for XIST RNA and H3K27me3, respectively.

    • Ryu-Suke Nozawa
    • Koji Nagao
    • Chikashi Obuse
  • In voltage-gated ion channels, transmembrane segments S3 and S4 are involved in voltage sensing and adopt a helix-turn-helix conformation, called the paddle motif, in crystal structures. Now extensive mutagenesis and electrophysiology analyses of the Shaker K+ channel demonstrate the physiological relevance of the paddle motif and dissect the roles of each segment in voltage sensing.

    • Yanping Xu
    • Yajamana Ramu
    • Zhe Lu
  • The secondary structure of mRNAs can slow or even halt protein synthesis. Single-molecule FRET studies of distinct steps in the translation elongation cycle now reveal that unfolding of mRNA secondary structures is more closely coupled to tRNA dissociation from the ribosomal exit site, with little effect on tRNA translocation within the ribosome.

    • Chunlai Chen
    • Haibo Zhang
    • Yale E Goldman
  • When the proapoptotic effector proteins BAX and BAK bind the BH3 domain of BID or BIM, they undergo conformational changes and oligomerization followed by insertion into the mitochondrial outer membranes, which leads to their permeabilization and, eventually, apoptosis. The NMR structure of the human BID BH3–BAK complex now provides structural insight into BAK activation.

    • Tudor Moldoveanu
    • Christy R Grace
    • Douglas R Green
  • Structure-specific endonucleases are essential to resolve DNA-replication and repair intermediates, but their uncontrolled activity would compromise genomic stability. New data show that the Holliday junction resolvase Mus81–Eme1 is activated in response to DNA damage by sequential phosphorylation by cell cycle– and DNA damage–dependent Cdc2CDK1 and Chk1 kinases, revealing how dual control restricts endonuclease activity in mitosis.

    • Pierre-Marie Dehé
    • Stéphane Coulon
    • Pierre-Henri L Gaillard
  • The signal recognition particle (SRP) targets nascent proteins with hydrophobic signal sequences to translocation machineries at the target membrane. Structural, thermodynamic and kinetic studies of a 'false' early complex, formed by SRP and its receptor with ribosomes translating an incorrect cargo, suggest an unstable complex that rearranges inefficiently into subsequent conformational states, resulting in receptor dissociation rather than successful targeting.

    • Ottilie von Loeffelholz
    • Kèvin Knoops
    • Christiane Schaffitzel
  • The CDK8 kinase module (CKM) is a subcomplex that interacts with Mediator and represses transcription. Structural and biochemical analyses now show that interaction of the CKM with Mediator interferes with C-terminal domain–dependent binding of RNA polymerase II to a previously unknown Mediator binding site and with holoenzyme formation, which forms the basis for CKM's repressive effect on transcription.

    • Kuang-Lei Tsai
    • Shigeo Sato
    • Francisco J Asturias
  • Translation initiation factor 3 (IF3) regulates the fidelity with which the initiator tRNA and mRNA start codon substrates are selected into the 30S ribosomal subunit initiator complex (30S IC). Single-molecule FRET analyses now suggest the existence of a conformational selection mechanism by which a single conformation of IF3 is stabilized through proper substrate selection.

    • Margaret M Elvekrog
    • Ruben L Gonzalez Jr
  • Glutamate transporters translocate their substrate-binding site across the membrane, in a cycle fueled by the energy of the sodium gradient. Now GltPh is trapped by cross-linking, with its substrate-binding site facing inward or outward, to reveal that the Na+ potential is coupled to substrate binding and release, not to substrate translocation.

    • Nicolas Reyes
    • SeCheol Oh
    • Olga Boudker
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Brief Communication

  • Post-translational modifications of tRNAs can alter their decoding specificity. A molecular basis for altered codon specificity is now provided by the crystal structure of the archaeal tRNA2Ile modified with agmatidine at the wobble cytidine residue in complex with the AUA codon on the ribosome.

    • Rebecca M Voorhees
    • Debabrata Mandal
    • V Ramakrishnan
    Brief Communication
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