News & Views

  • News & Views |

    The multisubunit phospholipid transport system Mla has been under scrutiny to determine whether it functions as an exporter or an importer. Structural studies accompanied by the reconstitution of the entire Mla system into proteoliposomes now reveal that ATP binding and hydrolysis drive phospholipid import.

    • Russell E. Bishop
  • News & Views |

    The protein SARM1 is an executioner of axon degeneration through its NAD+ hydrolase activity. Three groups now report structures of human SARM1 in an inactive state and identify NAD+ as an allosteric inhibitor, illuminating an elegant mechanism of how SARM1 is activated at lower NAD+ levels and causes NAD+ collapse and axon degeneration.

    • Liang Tong
  • News & Views |

    Three recent studies report cryo-EM structures of amyloid fibrils of islet amyloid polypeptide (IAPP), which are linked to type 2 diabetes (T2D) pathogenesis. The results shed light on the structural basis of IAPP fibril formation, reveal remarkable similarities between IAPP and Aβ fibrils and will inform the design of anti-amyloid drugs in T2D and Alzheimer’s disease (AD).

    • Aphrodite Kapurniotu
  • News & Views |

    BAX and BAK oligomerize to mediate mitochondrial membrane permeabilization during apoptosis. A recent structure of the core domain of active BAK dimers with bound phospholipid molecules reveals a new bridging mechanism by which lipids drive BAX and BAK oligomerization and membrane pore formation.

    • Hector Flores-Romero
    •  & Ana J. García-Sáez
  • News & Views |

    In situ structures of the spirochete flagellar motor by cryo-ET reveal two distinct modes of interactions between the rotor ring and stator units. Together with new cryo-EM structures of the isolated stator units, this work provides insights into the mechanisms of torque generation and directional switch.

    • Keiichi Namba
  • News & Views |

    During translesion synthesis, eukaryotic DNA polymerase ζ carries out extension from a wide range of DNA lesions. Elucidation of the cryo-EM structure of polymerase ζ reveals how the enzyme catalyzes DNA strand synthesis beyond the lesion.

    • M. Todd Washington
    •  & Melissa S. Gildenberg
  • News & Views |

    A new cryo-EM structure of mitochondrial complex I reveals ordered water molecules that connect key elements of the proton-translocating machinery. Analysis of the ubiquinone-binding site of complex I offers insights into the mechanism of catalytic turnover and the regulation of this essential metabolic enzyme.

    • Alexander Galkin
  • News & Views |

    Visualizing siRNA targeting of single mRNAs in living cells reveals that passing ribosomes temporarily unfold the mRNA, exposing it to siRNA recognition. This effect is due to the slow reorganization of many weak, suboptimal interactions within the mRNA.

    • Ewelina M. Małecka
    •  & Sarah A. Woodson
  • News & Views |

    The cell surface protein CD4 acts as a coreceptor for incoming HIV particles. However, the expression of CD4 in HIV-producing cells is detrimental to virus propagation and pathogenicity. To solve this issue, the viral accessory protein Nef forces CD4 endocytosis and targets it for lysosomal degradation. Structural elucidation of the AP-2–Nef–CD4 complex shows how Nef connects CD4 to the clathrin endocytic machinery, revealing a potential new target for anti-HIV therapy.

    • Yunan C. Januário
    •  & Luis L. P. daSilva
  • News & Views |

    The nuclear piRNA pathway safeguards genome integrity in the germline by silencing transposable elements. Three recent studies have identified new players in the mammalian pathway. Two of these, TEX15 and SPOCD1, might provide a link between piRNA-guided complexes that recognize genomic targets and the molecular machinery that induces DNA methylation and transcriptional repression during mouse spermatogenesis.

    • Maria Ninova
    •  & Katalin Fejes Tóth
  • News & Views |

    Translation and mRNA decay are tightly connected processes governing protein production, and their regulation involves an elaborate network of protein factors and sequence elements. A massively parallel RNA-based reporter system now reveals regulatory pathways triggered by 5′ UTR elements and allows dissection of the interplay between translation and mRNA decay.

    • Marc Bühler
    •  & Alex Charles Tuck
  • News & Views |

    Cellular protein levels are finely tuned through microRNA-mediated gene regulation, triggered by RNA-induced silencing complexes (RISCs) that recognize, bind and silence mRNA targets. A recent study shows that, while mRNA target recognition is achieved with only about a third of the guide RNA sequence, formation of an efficient RISC conformation required for target silencing involves the coordination of transient structural states of the entire guide RNA–mRNA duplex.

    • François Major
  • News & Views |

    How Gram-negative bacteria transport glycerophospholipids between membranes remains a major point of inquiry for cell envelope biologists. Two groups report cryo-EM structures and functional studies of LetB (YebT), providing support for its involvement in cell envelope maintenance.

    • Matthew J. Powers
    •  & M. Stephen Trent
  • News & Views |

    Cryptochrome (CRY) photoreceptors undergo photoresponsive homo-oligomerization to become physiologically active, and BICs (blue-light inhibitors of CRYs) suppress homo-oligomerization. Structural elucidation of CRY–CRY homo-oligomers and a CRY–BIC heterodimer reveals how the activity of plant CRYs is regulated by alternative protein–protein interactions.

    • Qin Wang
    •  & Chentao Lin
  • News & Views |

    Poly-(ADP-ribosylation) is a post-translational modification with broad roles in cell signaling. A recently reported crystal structure reveals how the accessory factor HPF1 extends the catalytic active site of PARP1 and PARP2 to promote the specific ADP-ribosylation of serine residues, a prerequisite for dynamic chromatin changes induced by DNA damage.

    • Charlotte Blessing
    •  & Andreas G. Ladurner
  • News & Views |

    Adenosine deaminases acting on RNA (ADARs) catalyze deamination of adenosine to inosine. irCLASH identifies dsRNA substrates of ADARs and defines new features of their RNA-binding and editing activity, improving our understanding of these enzymes and aiding with future therapeutic applications.

    • Riccardo Pecori
    •  & Nina F. Papavasiliou
  • News & Views |

    Recent studies report the first structures of two CALHM family members, describing unexpected oligomeric architecture and providing insights into the mechanism of function of CALHM channels.

    • J. Kevin Foskett
  • News & Views |

    Many AAA+ ATPases assemble as hexamers to unfold protein substrates using a hand-over-hand, threading mechanism, but the Bcs1 AAA+ ATPase facilitates mitochondrial membrane translocation of the folded iron–sulfur Rieske protein. Two reports reveal that Bcs1 adopts an unusual heptameric configuration and provide insights into a non-canonical translocation mechanism.

    • Peter S. Shen
  • News & Views |

    Microbially derived peptides that mimic immunogenic gliadin peptides in celiac disease have been identified using a structure- and sequence-guided search. T cell activation assays and crystal structures reveal that a protein from the commensal bacterium Pseudomonas fluorescens can be processed and presented by antigen-presenting cells to potently activate T cells from patients with celiac disease.

    • Elena F. Verdu
    •  & Detlef Schuppan
  • News & Views |

    A study reports the structures of membrane-bound flavin-containing monooxygenases (FMOs), solved using reconstructed ancestral mammalian FMOs. The models provide a structural basis for these enzymes’ mechanism of action and show how the proteins interact with membranes and how substrates access their active sites.

    • Ian R. Phillips
    •  & Elizabeth A. Shephard
  • News & Views |

    Bacterial T-boxes are regulatory mRNA regions that control the transcription or translation of factors involved in amino acid supply. T-boxes act by directly binding to non-aminoacylated tRNA in response to amino acid starvation. Three studies now capture three-dimensional structures of tRNA–T-box complexes and reveal a set of RNA features that are required for the recognition of specific tRNAs and modulation of gene expression.

    • Jacob W. Weaver
    •  & Alexander Serganov
  • News & Views |

    Stabilization of the 3D genome architecture surrounding DNA lesions is critical for the maintenance of genome integrity. A new report by Ochs et al. shows how 53BP1 and RIF1 assemble a higher-order structure in the vicinity of damaged chromatin to protect it from unscheduled DNA-end resection.

    • Indrajeet Ghodke
    •  & Evi Soutoglou
  • News & Views |

    Finally, the architecture of the translocase of the mitochondrial outer membrane (TOM complex) is revealed, after 20 years of anticipation. Two groups have now determined the near-atomic structures of the TOM complex. These findings improve understanding of the mechanisms by which TOM facilitates the passage of about 1,000 different proteins from the cytosol into the mitochondria.

    • Doron Rapaport
  • News & Views |

    Segmented, double-stranded RNA viruses of the Reoviridae family tightly regulate the activity of encapsidated polymerases to mediate the transition between genome replication and iterative rounds of multipartite transcription within a particle. By resolving multiple in situ structures of the transcribing complex, a new study reveals enzyme conformational changes and RNA trajectories during specific transcriptional states that support an ‘ouroboros’ model of conservative transcription for a member of the Reoviridae family.

    • Kristen Ogden
  • News & Views |

    Chromatin is compartmentalized spatially and temporally at multiple levels, but the precise organization of chromatin and mechanisms underlying its restructuring remain unclear. Two studies published in Cell and Nature now demonstrate the ability of chromatin to undergo liquid–liquid phase separation under physiological conditions and show that this intrinsic physicochemical property of chromatin can be regulated.

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

    Upregulation of the X chromosome compensates for the presence of a single active X chromosome in mammals, but this has been difficult to measure and to understand mechanistically. A study now demonstrates that increased burst frequency boosts the transcriptional output of X-linked genes in male and female cells with a single active X chromosome. Interestingly, female embryonic stem cells lack increased burst frequency, which is established only after inactivation of the X chromosome takes place; this finding reveals a switch that can modulate transcriptional bursting.

    • Xinxian Deng
    •  & Christine M. Disteche
  • News & Views |

    A new cryo-EM structure of the bacterial flagellar hook, which connects the motor to the flagellar filament, reveals 11 distinctive conformations of the subunit. The cooperative dynamic switching among these states offers a dramatic extension of two-state models of protein allostery.

    • Edward H. Egelman
  • News & Views |

    Beige fat serves as a substantial metabolic sink that dissipates energy and has consequently attracted much attention as a target for improving metabolic health. A recent study has provided a new molecular target, the N-terminal acetyltransferase Naa10p, for harnessing beige-fat biogenesis and improving whole-body energy homeostasis1.

    • Qiang Wang
    •  & Shingo Kajimura
  • News & Views |

    The ‘N-end rule’ correlates the identity of the N-terminal residue of a protein to its in vivo half-life. A study has now shown that an N-terminal glycine can serve as a potent degradation signal, which reveals a novel branch of N terminus–dependent protein degradation.

    • Mohamed Eldeeb
    • , Mansoore Esmaili
    •  & Richard Fahlman
  • News & Views |

    Small RNAs guide nuclear Argonaute proteins to silence genomic target loci via recruitment of factors that lead to formation of repressive heterochromatin. Animal gonads use this pathway to repress transposable elements with PIWI-clade Argonaute proteins and their associated small RNAs called PIWI-interacting RNAs (piRNAs). Four research groups now identify a protein complex that acts as a molecular bridge between the piRNA pathway and the epigenetic silencing machinery.

    • David Homolka
    •  & Ramesh S. Pillai
  • News & Views |

    Researchers have sought to understand the function and regulation of the motor protein dynein since its discovery more than 50 years ago1. Dynein-2 is one of the motors that move the intraflagellar transport (IFT) trains ― large protein complexes that are needed for the assembly and function of eukaryotic cilia and flagella. Toropova et al. report the single-particle cryo-EM structure of the human dynein-2 complex2, which unexpectedly reveals two different conformations of the motor subunit tails. One tail forms a zigzag that matches the periodicity of the IFT trains, which reinforces the auto-inhibition of dynein motor activity and the binding of multiple dynein-2 complexes along the train during anterograde transport.

    • Susan K. Dutcher
  • News & Views |

    AAA ATPases constitute a large family of molecular chaperones, many of which unfold substrate proteins. Two recent cryo-EM studies of the AAA ATPase Cdc48 capture this enzyme in the midst of protein unfolding and reveal a universal substrate-threading mechanism for ring-shaped ATPases.

    • Yihong Ye
    •  & Di Xia
  • News & Views |

    The ability of CRISPR-Cas9 to accurately and efficiently target and cleave any segment of double-stranded DNA based solely on the sequence of its loaded guide RNA has revolutionized genome editing. While many structural studies have shed light on the atomic details of DNA targeting, structures of the enzyme poised to perform catalysis have remained elusive. In this issue, Zhu, Clarke, Puppala et al. provide snapshots of the enzyme in action as it performs concerted cleavage of a target DNA1.

    • David W. Taylor
  • News & Views |

    The ‘tubulin code’, a set of post-translational modifications to the microtubule cytoskeleton that include removal of the C-terminal Tyr of α-tubulin, regulates the biological function of the polymer. Three studies now report structures of VASH1–SVBP and VASH2–SVBP heterodimers and provide insights into how these proteases recognize and cleave the terminal Tyr of α-tubulin.

    • Kevin C. Slep
  • News & Views |

    Abasic sites are among the most frequent DNA lesions, and when they occur within single-stranded DNA, their repair can give rise to genomic instability and mutations. One mechanism for the protection of abasic sites involves covalent attachment of 5-hydroxymethylcytosine-binding, embryonic stem cell–specific (HMCES) protein to DNA. Now, two research groups have elucidated the structural basis of the action of HMCES and its bacterial equivalent, YedK, revealing a unique and intriguing chemistry of DNA–protein crosslink formation.

    • Marcin Nowotny
  • News & Views |

    Viral mRNA synthesis is an essential step in the influenza virus replication cycle and is a prime target for the development of new antivirals. New structures of the influenza virus RNA polymerase now unveil previously unknown details of influenza virus transcription.

    • Aartjan J. W. te Velthuis
  • News & Views |

    Two recent cryo-EM structures of the human L-type heteromeric amino acid transporter LAT1–CD98hc reveal surprising new insights into both amino acid transport in the human body and the roles of CD98hc as a cell-surface antigen and trafficking chaperone.

    • Simon Newstead
  • News & Views |

    Epigenetic memory of silent chromatin often requires robust feedback loops between factors processing small non-coding RNAs and enzymes involved in heterochromatin assembly. A study published in Molecular Cell now demonstrates that these feedback loops can persist in a phenotypically neutral state even when gene expression is reactivated, and that they maintain the potential to reinstall heterochromatin in later generations when conditions change.

    • Matías Capella
    •  & Sigurd Braun
  • News & Views |

    Cytosine methylation (m5C) is one of the more disputed base modifications of the epitranscriptome, mostly because current methods for detection are prone to artifacts. A new approach to increase detection accuracy reveals intriguing evidence of a role for the tRNA methyltransferase NSUN2 in the methylation of mRNA.

    • Lukas Trixl
    •  & Alexandra Lusser
  • News & Views |

    In the ribosome-associated quality control (RQC) pathway, stalled ribosomes are ubiquitinated and dissociated into subunits. The nascent protein chain associated with the 60S ribosomal subunit is ubiquitinated by the E3 ligase Listerin (Ltn1) and is released from tRNA by ANKZF1 (Vms1) for proteasomal degradation. Shao and colleagues now report that ANKZF1 (Vms1)-cleaved tRNAs are recycled via a two-step process that requires the removal of a terminal 2′,3′-cyclic phosphate and the addition of CCA by TRNT1.

    • Toshifumi Inada
  • News & Views |

    Ribonucleotides that are misincorporated into DNA during replication are removed by topoisomerase 1, which generates 3′-terminal adducts that are not amenable to DNA repair and thus compromise genome stability. A recent report by Li et al. reveals that Apn2/APE2 resolves such blocked 3′ termini, thereby suppressing topoisomerase 1–induced mutations at ribonucleotide monophosphate sites within the genome.

    • Shan Yan
  • News & Views |

    RNAs perform diverse cellular functions that are mediated at least in part by their structure. However, how RNA structure changes throughout the RNA lifecycle and how these changes affect RNA function remain incompletely understood. A detailed in vivo characterization of RNA structure in various cellular subcompartments now provides insights into how RNA structural changes influence translation, RNA decay, protein binding and RNA modification.

    • Angela M Yu
    •  & Julius B. Lucks
  • News & Views |

    Intertwining of DNA molecules frequently results in the formation of ‘ultrafine bridges’ between sister chromatids that need to be resolved during segregation of the chromatids into daughter cells. Although it has been established that these DNA bridges are coated by the helicase PICH, it has remained unknown how PICH assists in their resolution. A study now reveals that PICH directs the formation of positive DNA supercoiling in the presence of type I topoisomerases to promote the subsequent disentanglement of these DNA helices by type II topoisomerases. Remarkably, PICH might be able to reconfigure DNA topology by extruding loops of DNA while it moves along the double helix.

    • Shveta Bisht
    •  & Christian H. Haering
  • News & Views |

    Chromatin organization in the nucleus plays an important role in cell-type-specific gene expression. A new study reports reconstruction of the 3D genome in single sensory neurons and provides insights into the regulation of genes encoding odorant receptors.

    • Lúcia M. Armelin-Correa
    •  & Bettina Malnic
  • News & Views |

    Bacteriophage-encoded anti-CRISPR (Acr) proteins were previously thought to inhibit CRISPR-mediated immunity by acting as physical barriers against the binding or cleavage of DNA. Two new studies report that recently discovered type V Acr proteins use enzymatic activities to shut down the Cas12a endonuclease, providing a multi-turnover ‘off switch’ for CRISPR-based immunity and technology.

    • Shravanti K. Suresh
    • , Karthik Murugan
    •  & Dipali G. Sashital
  • News & Views |

    Ubiquitin and ubiquitin-like proteins (UBLs) are essential regulators of a multitude of cellular processes, including autophagy. It is known that these proteins relay their effects by covalently modifying their substrate molecules. As an exception to this norm, Pang et al. report a novel phenomenon in which the UBL ATG12 interacts with its substrate ATG5 in a non-covalent fashion to promote autophagy in apicomplexan parasites and some yeasts.

    • Varnesh Tiku
    •  & Ivan Dikic