News & Comment

  • News & Views |

    The σ1 receptor, an endoplasmic reticulum–resident transmembrane protein, modulates many physiological and pathological processes and binds multiple drugs, but is nonetheless poorly understood. In a recent issue, Kruse and colleagues illustrate structural differences between agonist- and antagonist-bound receptor and propose that agonist binding may impair oligomerization, making a major step in understanding σ1 function. They also use a combination of kinetic and molecular dynamic modeling to explain how ligands access the binding pocket.

    • Felix J. Kim
    •  & Gavril W. Pasternak
  • News & Views |

    RNA uridylation offers a basis for diverse post-transcriptional regulation. Two recent studies reveal new roles of uridylation in immune defense against viruses and retrotransposons.

    • Jinah Yeo
    •  & V. Narry Kim
  • Meeting Report |

    A symposium in June 2018 sponsored by the Center on Membrane Protein Production and Analysis, a unit of the New York Structural Biology Center, focused on the structures of proteins residing in biological membranes. Explicit emphasis was placed on currently developing technologies aimed at determining such structures and at understanding their dynamics, mechanisms and complex interactions.

    • Chris Miller
  • News & Views |

    The effects of RNA secondary structure on translation have been well recognized; however, the global interplay between both in a dynamic cellular system is poorly understood. Beaudoin, Giraldez and colleagues have analyzed RNA structure dynamics during zebrafish embryonic development and have found that the ribosome unzips mRNA secondary structure during translation, thus leading to a global decrease of structure in highly translated transcripts. Furthermore, the authors establish RNA structure in the 3′ untranslated regions of mRNAs as a major regulator of transcript stability in this context.

    • Marianne C. Kramer
    •  & Brian D. Gregory
  • News & Views |

    The mechanism underlying CCG-repeat expansions in patients with fragile X premutation is not well understood. Using a new experimental system in mammalian cells, a study in this issue reports that break-induced replication has a role in CGG-repeat instability.

    • Madhura Deshpande
    •  & Jeannine Gerhardt
  • News & Views |

    A series of new cryo-EM structures reveals a surprising twist in how the RAG complex initiates V(D)J recombination. The initial complex with substrate DNA adopts two conformations: in one, the DNA is relatively undistorted but the scissile phosphate is far from the active site, and in the other the DNA is partially melted and unwound by half a turn, which allows the scissile phosphate to dock into the active site. Similar pre-catalysis DNA melting may occur with other DDE recombinases, for which equivalent complexes with uncleaved substrate DNA are not yet available.

    • Fred Dyda
    •  & Phoebe A. Rice
  • News & Views |

    Under steady-state conditions, the E3 ubiquitin ligase Parkin is localized to the cytosol in an autoinhibited state. Two recent studies describe the mechanism of Parkin activation by phosphorylation via structural rearrangement of the Ubl and RING2 domains, explaining how the RING2 domain is released from the core of Parkin to allow for ubiquitination of its substrates.

    • François Le Guerroué
    •  & Richard J. Youle
  • News & Views |

    In a stress-free environment, the histone binding function of 53BP1 is inhibited by TIRR, but upon DNA damage 53BP1 is recruited to chromatin and promotes DNA repair. New structural studies provide insights into the mechanisms underlying 53BP1 inhibition and activation. TIRR physically blocks the methyl-lysine histone-binding site of Tudors, and RNA binding by TIRR alleviates this block.

    • Yi Zhang
    •  & Tatiana G. Kutateladze
  • News & Views |

    Activation signals from GPCRs, the largest receptor family, are transmitted to heterotrimeric G proteins and arrestins, and can be differentially modulated by GPCR phosphorylation. In a recent article, available data, including multiple arrestin structures, are analyzed to decipher common and state-specific conformational changes in arrestins and how these depend on patterns of receptor phosphorylation.

    • Christopher J. Draper-Joyce
    •  & Arthur Christopoulos
  • News & Views |

    Traditional approaches to covalent drug design postulate that noncovalent binding affinity (Ki) should be in the nanomolar range for the lead compound to be attractive. A study by Hansen et al. suggests that covalent K-Ras inhibitors can have weak noncovalent binding affinity yet have fast chemical reactivity (kinact), because K-Ras enhances the covalent reactivity of bound inhibitor, similarly to how enzymes activate their substrates.

    • Alexander V. Statsyuk
  • News & Views |

    Recent developments in transcriptome-wide sequencing technologies have enabled the identification of cellular mRNA decay intermediates. Although canonical mRNA decay has been shown to occur by deadenylation followed by decapping and subsequent exonucleolytic decay from both mRNA ends, a study by Mourelatos and colleagues now defines mRNA fragments that are generated on polysomes by endonucleolytic cleavages phased by the associated ribosome.

    • Tatsuaki Kurosaki
    •  & Lynne E. Maquat
  • News & Views |

    Nanobodies have emerged as highly versatile and useful binding molecules in biomedical research. A technical report describes a cost- and time-effective in vitro platform that facilitates the generation of desired nanobodies, including conformationally selective nanobodies against agonist-bound G-protein-coupled receptors (GPCRs).

    • Ulrich Rothbauer
  • News & Views |

    Inheritance of Polycomb repressive complex 2 (PRC2)-mediated gene silencing involves self-propagation of histone H3 lysine 27 (H3K27) methylation from an initial nucleation site, but how the first H3K27 methylation marks are established is not fully understood. A recent study reveals that PRC2 can reconstitute H3K27 methylation de novo in cells that have lost the mark. This reconstitution is dependent on the PRC2 core component SUZ12, which provides a novel link between initiation and self-propagation of this critical epigenetic mark.

    • Jafar Sharif
    •  & Haruhiko Koseki
  • News & Views |

    A new study reveals how the oocyte-specific transcription factor TAp63 ensures female germ line fidelity and describes approaches to circumvent premature ovarian insufficiency in women receiving cytotoxic chemotherapy.

    • Wa Xian
    •  & Frank McKeon
  • News & Views |

    Transcripts with highly complementary sequences can target microRNAs (miRNAs) for degradation, but the physiological relevance of target-directed miRNA degradation (TDMD) has remained unclear. Bitetti et al. now identify a conserved vertebrate RNA that induces TDMD in the cerebellum of zebrafish and mouse to promote wild-type animal behaviors.

    • Manuel de la Mata
    •  & Helge Großhans
  • News & Views |

    Chd1 is a highly conserved chromatin remodeler found across all eukaryotic species. A recent study shows the structural changes that take place when yeast Chd1 binds to its nucleosomal substrate and reveals how they relate to remodeler function.

    • Michaela M. Smolle
  • Editorial |

    This January 2018 issue starts the 25th year of NSMB’s journey. We mark the occasion by launching a special series that celebrates the exciting research uncovering the fundamental principles behind biological processes.

  • News & Views |

    The helicase intrinsic to DNA polymerase θ (Polθ), the versatile mediator of microhomology-based repair of DNA double-strand breaks and stalled replication forks, is now revealed to be a member of an elite group of proteins known as annealing helicases. This small family of enzymes remodels DNA intermediates in multiple repair processes that are crucial to preserving genome stability and warding off cancer and aging.

    • Judith L Campbell
    •  & Hongzhi Li
  • News & Views |

    The crystal structure of an oligosaccharyltransferase in complex with a sugar donor and an acceptor peptide provides insight into the mechanism of protein glycosylation and reveals how lipid-linked oligosaccharides are positioned in the enzyme active site.

    • Shiteshu Shrimal
    • , Natalia A Cherepanova
    •  & Reid Gilmore
  • News & Views |

    Deadenylation of mRNAs is generally associated with translational inhibition and mRNA decay. A study now reports that, unexpectedly, highly expressed genes tend to have shorter poly(A) tails and suggests that poly(A) tails can be 'pruned', generating a 30-nucleotide-biased phased distribution, likely due to protection by poly(A)-binding proteins.

    • Luciana A Castellano
    •  & Ariel A Bazzini
  • News & Views |

    Assembly of the small ribosomal subunit from an RNA strand and 33 proteins is an intricate and dynamic process. Two cryo-EM studies now provide insight into a complicated complex of at least 51 trans-factors that act on the preribosomal small subunit to sequentially fold it into a 3D molecular machine.

    • Joanna Rorbach
    • , Shintaro Aibara
    •  & Alexey Amunts
  • News & Views |

    C-type inactivation is a process by which ion flux through a voltage-gated K+ channel is regulated at the selectivity filter. A recent structure of the Kv1.2 channel provides a view into the structural changes of the selectivity filter during C-type inactivation.

    • Francis I Valiyaveetil
  • News & Views |

    PERK is a major sensor of the unfolded protein response controlling cell fate under endoplasmic reticulum (ER) stress. A new study reveals an additional step for optimal PERK signaling, involving the binding of CNPY2 to PERK's luminal domain. The PERK–CNPY2 axis was shown to enhance cell death under ER stress in vivo influence liver disease.

    • Hery Urra
    •  & Claudio Hetz
  • News & Views |

    PCSK9 enhances LDL cholesterol (LDL-c) levels by escorting the liver LDL receptor (LDLR) to endosomes and lysosomes for degradation. PCSK9 monoclonal antibodies and RNA-antisense formulations are effective in reducing LDL cholesterol in patients. The recent structural identification of a novel pocket in PCSK9 paves the way to the future development of orally active small-molecule hypocholesterolemic drugs.

    • Nabil G Seidah
  • News & Views |

    The cellular crosstalk between different classes of regulatory noncoding RNAs has reached a new spatial dimension. Jiang et al. reveal an essential role of a nuclear-paraspeckle-organizing long noncoding RNA and its protein partners in regulating the first steps of microRNA biogenesis.

    • Jacek Krol
  • News & Views |

    The monoallelic expression of many imprinted genes in mammals depends on DNA methylation marks that originate from the germ cells. Recent studies in mice and fruit flies evoke a novel, transient mode of genomic imprinting in which oocyte-acquired histone H3 Lys27 trimethylation (H3K27me3) marks are transmitted to the zygote and modulate the allele specificity and timing of gene expression in the early embryo.

    • Rakesh Pathak
    •  & Robert Feil
  • News & Views |

    The robustness of the circadian clock deteriorates with aging. Two new studies show that aging reprograms the circadian transcriptome in a cell-type-dependent manner and that such rewiring can be reversed by caloric restriction.

    • Rika Ohkubo
    •  & Danica Chen
  • News & Views |

    Group II chaperonins facilitate protein folding by undergoing ATP-driven conformational changes. A recent study reveals a tunable allosteric network in group II chaperonins that includes a residue at the intersubunit interface, which is important for assembly and allosteric coordination. The authors also propose that lower cooperativity allows group II chaperonins to achieve optimal substrate folding over a broad range of ATP concentrations.

    • Mingliang Jin
    •  & Yao Cong
  • News & Views |

    Meiotic progression is controlled by cytoplasmic polyadenylation and translational activation of masked, maternal mRNAs. RNA-binding-protein interactions with adjacent cis elements cause local conformational changes to the mRNAs that determine the extent and timing of their activation.

    • Paul Lasko
  • News & Views |

    An unusual pairing of homologous X chromosomes occurs during X inactivation. A new study in mouse embryonic stem cells shows that telomeres and the telomeric RNA PAR-TERRA are responsible for additional pairwise interactions that guide Xic–Xic pairing.

    • Ivan Krivega
    •  & Ann Dean
  • News & Views |

    The envelope glycoprotein spike, the sole antigen on the Lassa virus (LASV) surface, constitutes the focal point of the host neutralizing immune response. A high-resolution structure of the trimeric LASV glycoprotein in an antibody-bound form illuminates the molecular architecture of the antigen and reveals the mode of action of the most abundant known class of Lassa-specific human neutralizing antibodies.

    • Antra Zeltina
    •  & Thomas A Bowden
  • News & Views |

    Cytoplasmic dyneins transport cellular components from the periphery toward the center of the cell. By moving cargoes along microtubules, dyneins ensure proper cell division, regulate exchange of materials between organelles, and contribute to the internal organization of eukaryotic cells. Two recent studies show that, upon dimerization, cytoplasmic dyneins intrinsically adopt an autoinhibited configuration that can be relieved by other factors to precisely control motor activity and regulate dynein-based transport.

    • Gaia Pigino
    •  & Stephen M King
  • News & Views |

    Long noncoding (lnc)RNAs are postulated to control diverse biological processes by modulating transcription, yet for most lncRNAs evidence supporting this function has been lacking. A new report describes the role of a novel class of lncRNAs—chromatin-associated enhancer RNAs or cheRNAs—in the regulation of proximal gene expression.

    • Srimonta Gayen
    •  & Sundeep Kalantry
  • Editorial |

    Nature research journals announce new reporting summaries to promote transparency, and our editors welcome early-career researchers to the Springer Nature office in New York to discuss careers in scientific publishing.

  • News & Views |

    Two new studies show that RNA-binding proteins can mediate distinct and beneficial effects to cells by binding to the extensive double-stranded RNA (dsRNA) structures of inverted-repeat Alu elements (IRAlus). One study reports stress-induced export of the 110-kDa isoform of the adenosine deaminase acting on RNA 1 protein (ADAR1p110) to the cytoplasm, where it binds IRAlus so as to protect many mRNAs encoding anti-apoptotic proteins from degradation. The other study demonstrates that binding of the nuclear helicase DHX9 to IRAlus embedded within RNAs minimizes defects in RNA processing.

    • Reyad A Elbarbary
    •  & Lynne E Maquat
  • News & Views |

    Interaction with heterotrimeric G proteins is a hallmark of G-protein-coupled receptor (GPCR) family members, and it is the key step for a diverse range of cell-signaling cascades. A recent cryo-EM structure of the human calcitonin receptor (CTR) in complex with a G-protein heterotrimer reveals novel insights into receptor–G-protein coupling.

    • Mithu Baidya
    • , Hemlata Dwivedi
    •  & Arun K Shukla
  • Meeting Report |

    The number of conferences on epigenetics has been increasing in the past decade, underscoring the impact of the field on a variety of areas in biology and medicine. However, the mechanistic role of the epigenome in adaptation and inheritance, and how the environment may impinge on epigenetic control, are topics of growing debate. Those themes were the focus of the inaugural international King Abdullah University of Science and Technology (KAUST) Research Conference on Environmental Epigenetics in Saudi Arabia, where more than 100 participants from 19 countries enjoyed vibrant scientific discussions and a pleasant February breeze from the Red Sea.

    • Mo Li
    • , Emiliana Borrelli
    • , Pierre J Magistretti
    • , Juan Carlos Izpisua Belmonte
    • , Paolo Sassone-Corsi
    •  & Valerio Orlando
  • News & Views |

    Chromatin remodelers are ATP-driven enzymes that can slide nucleosomes along DNA. Chen and colleagues present a tantalizing 4-Å view of the SWI/SNF ATPase motor bound to the nucleosome, which offers novel structural clues into the remodeling process.

    • Dale B Wigley
    •  & Gregory D Bowman
  • News & Views |

    The spatial organization of the genome profoundly influences how genes are regulated in normal development or dysregulated in disease. A new study of the murine HoxB locus illustrates how promoter interactions direct higher-order chromatin folding.

    • Swastika Sanyal
    • , Lucia Molnarova
    •  & Juraj Gregan
  • News & Views |

    One of the striking features of cells seen through a microscope is the heterogeneous organization of the nuclei. A combination of molecular methods and computational modeling has now been used to reconstruct accurate 3D structures of the genome inside single nuclei.

    • Elzo de Wit