Reviews & Analysis

At last, structures have been solved for different conformational states, facing in and facing out, for the same transporter protein of the major facilitator superfamily. The structural basis of alternating substrate access for binding and translocation can now be properly visualized.

Eukaryotic mRNAs containing nonsense codons are degraded by nonsense-mediated mRNA decay (NMD). In humans, NMD was proposed to act exclusively on newly synthesized mRNA during a 'pioneer round' of translation, when mRNA is associated with the nuclear cap-binding complex (CBC). Two reports now challenge this view, revealing that NMD is independent of whether CBC or the cytoplasmic cap-binding protein (eIF4E) promotes translation and can occur later in an mRNA's life.

Two structural variants of the RNaseH-like domain of the highly conserved spliceosomal protein Prp8 are correlated with Prp8 mutants that stabilize either the first- or second-step active sites of the spliceosome.

Whereas post-translational modifications (PTMs) in histone tails are well characterized, functional and mechanistic insights into PTMs in the globular nucleosome core have been lacking. This Perspective covers recent advances in the understanding of lateral-surface PTMs and their effects on nucleosome and chromatin dynamics.

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.

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.

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.

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.

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.

Macrodomains are conserved globular domains that can interact with, and in some cases modify, ADP-ribose–based molecules. In this issue, two reports add to the functional repertoire of this domain, by demonstrating that a subset of macrodomain-containing proteins functions to catalyze the removal of protein-proximal ADP-ribose.

The three-dimensional structure of a key complex in chaperone-mediated protein disaggregation, comprising ClpB and DnaK, has been determined using NMR. In addition to providing unique mechanistic insights, the approach promises to elucidate the structural basis for the assembly of elusive dynamic protein machineries in the near future.

Nuclear actin is a subunit of several chromatin-remodeling complexes, and the efficient binding of INO80 to extranucleosomal DNA is now shown to require actin. The form of actin present in the INO80 complex is monomeric and cannot associate with actin filaments.

To ensure replication success, DNA polymerases must negotiate encounters with actively transcribing RNA polymerases that share the genome. This Review highlights the strategies used by prokaryotic and eukaryotic cells to minimize the consequences of collisions between replication forks and transcription complexes to effect faithful DNA replication without compromising gene expression.

SMC (structural maintenance of chromosomes) protein complexes act in chromosome processing in all domains of life. In this issue, a study of the prokaryotic SMC complex Smc–ScpAB reveals an unanticipated asymmetry despite Smc forming a symmetric homodimer. This asymmetry—contributed by two distinct binding sites in Smc for the kleisin ScpA—is crucial for function in vivo and bears similarities to the eukaryotic complexes formed by Smc heterodimers.

Pluripotent cells have been derived from the inner cell mass of mouse embryos and also from primordial germ cells. A new study shows that cell lines of both origins exhibit highly similar transcriptomes and surprisingly low DNA methylation levels when maintained in culture conditions that support naive pluripotency. These 2i conditions thus provide a closer approximation of in vivo development and new insights into the regulation of DNA methylation.

Dynamic supercoiling is a steady-state mechanical regulatory mechanism that influences DNA topology, transcription factor binding, gene expression, chromatin structure and long-range chromosome interactions. How genes and nongene regions are organized into supercoiled domains and remodeled by transcriptional activity in human cells has now been analyzed in two large-scale studies at the chromosome and genome levels, providing new insight into the organization and expression of genes within chromosomes.

Structural and functional analyses of three neutralizing antibodies against influenza virus H2 HA may explain why this HA subtype has disappeared from circulation in the human population and point to a potential new avenue for antiflu therapeutics.

Global erasure and re-establishment of chromatin-based and DNA-based epigenetic marks occurs naturally in the mammalian life cycle, but it can also be artificially engineered using various reprogramming strategies. In this Review, recent advances in understanding how epigenetic remodeling contributes to cell-fate reprogramming in vivo and in vitro are summarized.

The properties of nucleosomes can be altered in various ways, including by covalent modification of histones. In this Review, the known properties of key histone modifications and the biological processes to which they are linked are examined to place the modifications in the context of nucleosome dynamics—that is, processes in which nucleosomes are translocated, unwrapped, evicted or replaced.