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Nature Structural & Molecular Biology

Tatsuaki Kurosaki, Lynne E Maquat
No abstract text is available yet for this article.
March 19, 2018: Nature Structural & Molecular Biology
Marcello Clerici, Marco Faini, Lena M Muckenfuss, Ruedi Aebersold, Martin Jinek
In the version of this article initially published online, an incorrect accession code PDB 6FN9 was introduced in Methods, in the 'Model building' section, line 2. This has been corrected to PDB 6F9N. The error has been corrected in the PDF and HTML versions of this article.
March 14, 2018: Nature Structural & Molecular Biology
Jocelyn Charlton, Timothy L Downing, Zachary D Smith, Hongcang Gu, Kendell Clement, Ramona Pop, Veronika Akopian, Sven Klages, David P Santos, Alexander M Tsankov, Bernd Timmermann, Michael J Ziller, Evangelos Kiskinis, Andreas Gnirke, Alexander Meissner
Cytosine methylation is widespread among organisms and essential for mammalian development. In line with early postulations of an epigenetic role in gene regulation, symmetric CpG methylation can be mitotically propagated over many generations with extraordinarily high fidelity. Here, we combine BrdU labeling and immunoprecipitation with genome-wide bisulfite sequencing to explore the inheritance of cytosine methylation onto newly replicated DNA in human cells. Globally, we observe a pronounced lag between the copying of genetic and epigenetic information in embryonic stem cells that is reconsolidated within hours to accomplish faithful mitotic transmission...
March 12, 2018: Nature Structural & Molecular Biology
Elizabeth L Guenther, Peng Ge, Hamilton Trinh, Michael R Sawaya, Duilio Cascio, David R Boyer, Tamir Gonen, Z Hong Zhou, David S Eisenberg
Proteins in the fibrous amyloid state are a major hallmark of neurodegenerative disease. Understanding the multiple conformations, or polymorphs, of amyloid proteins at the molecular level is a challenge of amyloid research. Here, we detail the wide range of polymorphs formed by a segment of human TAR DNA-binding protein 43 (TDP-43) as a model for the polymorphic capabilities of pathological amyloid aggregation. Using X-ray diffraction, microelectron diffraction (MicroED) and single-particle cryo-EM, we show that the247 DLIIKGISVHI257 segment from the second RNA-recognition motif (RRM2) forms an array of amyloid polymorphs...
March 12, 2018: Nature Structural & Molecular Biology
Fadia Ibrahim, Manolis Maragkakis, Panagiotis Alexiou, Zissimos Mourelatos
mRNAs transmit the genetic information that dictates protein production and are a nexus for numerous pathways that regulate gene expression. The prevailing view of canonical mRNA decay is that it is mediated by deadenylation and decapping followed by exonucleolysis from the 3' and 5' ends. By developing Akron-seq, a novel approach that captures the native 3' and 5' ends of capped and polyadenylated RNAs, respectively, we show that canonical human mRNAs are subject to repeated cotranslational and ribosome-phased endonucleolytic cuts at the exit site of the mRNA ribosome channel, in a process that we term ribothrypsis...
March 5, 2018: Nature Structural & Molecular Biology
Marcel Tuppi, Sebastian Kehrloesser, Daniel W Coutandin, Valerio Rossi, Laura M Luh, Alexander Strubel, Katharina Hötte, Meike Hoffmeister, Birgit Schäfer, Tiago De Oliveira, Florian Greten, Ernst H K Stelzer, Stefan Knapp, Massimo De Felici, Christian Behrends, Francesca Gioia Klinger, Volker Dötsch
The survival rate of cancer patients is steadily increasing, owing to more efficient therapies. Understanding the molecular mechanisms of chemotherapy-induced premature ovarian insufficiency (POI) could identify targets for prevention of POI. Loss of the primordial follicle reserve is the most important cause of POI, with the p53 family member p63 being responsible for DNA-damage-induced apoptosis of resting oocytes. Here, we provide the first detailed mechanistic insight into the activation of p63, a process that requires phosphorylation by both the priming kinase CHK2 and the executioner kinase CK1 in mouse primordial follicles...
February 26, 2018: Nature Structural & Molecular Biology
Zengqin Deng, Navid Paknejad, Grigory Maksaev, Monica Sala-Rabanal, Colin G Nichols, Richard K Hite, Peng Yuan
The transient receptor potential (TRP) channel TRPV4 participates in multiple biological processes, and numerous TRPV4 mutations underlie several distinct and devastating diseases. Here we present the cryo-EM structure of Xenopus tropicalis TRPV4 at 3.8-Å resolution. The ion-conduction pore contains an intracellular gate formed by the inner helices, but lacks any extracellular gate in the selectivity filter, as observed in other TRPV channels. Anomalous X-ray diffraction analyses identify a single ion-binding site in the selectivity filter, thus explaining TRPV4 nonselectivity...
February 26, 2018: Nature Structural & Molecular Biology
Jonas W Højfeldt, Anne Laugesen, Berthe M Willumsen, Helene Damhofer, Lin Hedehus, Andrey Tvardovskiy, Faizaan Mohammad, Ole N Jensen, Kristian Helin
Polycomb repressive complex 2 (PRC2) catalyzes methylation on lysine 27 of histone H3 (H3K27) and is required for maintaining transcriptional patterns and cellular identity, but the specification and maintenance of genomic PRC2 binding and H3K27 methylation patterns remain incompletely understood. Epigenetic mechanisms have been proposed, wherein pre-existing H3K27 methylation directs recruitment and regulates the catalytic activity of PRC2 to support its own maintenance. Here we investigate whether such mechanisms are required for specifying H3K27 methylation patterns in mouse embryonic stem cells (mESCs)...
February 26, 2018: Nature Structural & Molecular Biology
Liming Yan, Yuanbo Qi, Xiaofang Huang, Caiting Yu, Lan Lan, Xiangyang Guo, Zihe Rao, Junjie Hu, Zhiyong Lou
Fusion of the outer mitochondrial membrane is mediated by the dynamin-like GTPase mitofusin (MFN). Here, we determined the structure of the minimal GTPase domain (MGD) of human MFN1 in complex with GDP-BeF3 - . The MGD folds into a canonical GTPase fold with an associating four-helix bundle, HB1, and forms a dimer. A potassium ion in the catalytic core engages GDP and BeF3 - (GDP-BeF3 - ). Enzymatic analysis has confirmed that efficient GTP hydrolysis by MFN1 requires potassium. Compared to previously reported MGD structures, the HB1 structure undergoes a major conformational change relative to the GTPase domains, as they move from pointing in opposite directions to point in the same direction, suggesting that a swing of the four-helix bundle can pull tethered membranes closer to achieve fusion...
February 26, 2018: Nature Structural & Molecular Biology
Colin E Correnti, Mesfin M Gewe, Christopher Mehlin, Ashok D Bandaranayake, William A Johnsen, Peter B Rupert, Mi-Youn Brusniak, Midori Clarke, Skyler E Burke, Willem De Van Der Schueren, Kristina Pilat, Shanon M Turnbaugh, Damon May, Alex Watson, Man Kid Chan, Christopher D Bahl, James M Olson, Roland K Strong
Peptides folded through interwoven disulfides display extreme biochemical properties and unique medicinal potential. However, their exploitation has been hampered by the limited amounts isolatable from natural sources and the expense of chemical synthesis. We developed reliable biological methods for high-throughput expression, screening and large-scale production of these peptides: 46 were successfully produced in multimilligram quantities, and >600 more were deemed expressible through stringent screening criteria...
February 26, 2018: Nature Structural & Molecular Biology
Angelo Bitetti, Allison C Mallory, Elisabetta Golini, Claudia Carrieri, Héctor Carreño Gutiérrez, Emerald Perlas, Yuvia A Pérez-Rico, Glauco P Tocchini-Valentini, Anton J Enright, William H J Norton, Silvia Mandillo, Dónal O'Carroll, Alena Shkumatava
microRNAs (miRNAs) repress target transcripts through partial complementarity. By contrast, highly complementary miRNA-binding sites within viral and artificially engineered transcripts induce miRNA degradation in vitro and in cell lines. Here, we show that a genome-encoded transcript harboring a near-perfect and deeply conserved miRNA-binding site for miR-29 controls zebrafish and mouse behavior. This transcript originated in basal vertebrates as a long noncoding RNA (lncRNA) and evolved to the protein-coding gene NREP in mammals, where the miR-29-binding site is located within the 3' UTR...
February 26, 2018: Nature Structural & Molecular Biology
Danielle A Grotjahn, Saikat Chowdhury, Yiru Xu, Richard J McKenney, Trina A Schroer, Gabriel C Lander
In the version of this article initially published online, an incorrect accession code, EMD-5NW4, was introduced on page 1 of the article PDF, in section 'BICD2N mediates the association of two dynein dimers with a single dynactin'. This has been corrected to PDB 5NW4. The error has been corrected in the PDF and HTML versions of this article.
February 23, 2018: Nature Structural & Molecular Biology
Jiho Yoo, Ellene H Mashalidis, Alvin C Y Kuk, Kazuki Yamamoto, Benjamin Kaeser, Satoshi Ichikawa, Seok-Yong Lee
N-linked glycosylation is a predominant post-translational modification of protein in eukaryotes, and its dysregulation is the etiology of several human disorders. The enzyme UDP-N-acetylglucosamine:dolichyl-phosphate N-acetylglucosaminephosphotransferase (GlcNAc-1-P-transferase or GPT) catalyzes the first and committed step of N-linked glycosylation in the endoplasmic reticulum membrane, and it is the target of the natural product tunicamycin. Tunicamycin has potent antibacterial activity, inhibiting the bacterial cell wall synthesis enzyme MraY, but its usefulness as an antibiotic is limited by off-target inhibition of human GPT...
February 19, 2018: Nature Structural & Molecular Biology
Junhong Choi, Gabriele Indrisiunaite, Hasan DeMirci, Ka-Weng Ieong, Jinfan Wang, Alexey Petrov, Arjun Prabhakar, Gideon Rechavi, Dan Dominissini, Chuan He, Måns Ehrenberg, Joseph D Puglisi
Chemical modifications of mRNA may regulate many aspects of mRNA processing and protein synthesis. Recently, 2'-O-methylation of nucleotides was identified as a frequent modification in translated regions of human mRNA, showing enrichment in codons for certain amino acids. Here, using single-molecule, bulk kinetics and structural methods, we show that 2'-O-methylation within coding regions of mRNA disrupts key steps in codon reading during cognate tRNA selection. Our results suggest that 2'-O-methylation sterically perturbs interactions of ribosomal-monitoring bases (G530, A1492 and A1493) with cognate codon-anticodon helices, thereby inhibiting downstream GTP hydrolysis by elongation factor Tu (EF-Tu) and A-site tRNA accommodation, leading to excessive rejection of cognate aminoacylated tRNAs in initial selection and proofreading...
February 19, 2018: Nature Structural & Molecular Biology
Danielle A Grotjahn, Saikat Chowdhury, Yiru Xu, Richard J McKenney, Trina A Schroer, Gabriel C Lander
Cytoplasmic dynein is a protein complex that transports molecular cargo along microtubules (MTs), playing a key role in the intracellular trafficking network. Vertebrate dynein's movement becomes strikingly enhanced upon interacting with dynactin and a cargo adaptor such as BicaudalD2. However, the mechanisms responsible for increased transport activity are not well understood, largely owing to limited structural information. We used cryo-electron tomography (cryo-ET) to visualize the 3D structure of the MT-bound dynein-dynactin complex from Mus musculus and show that the dynactin-cargo adaptor complex binds two dimeric dyneins...
February 7, 2018: Nature Structural & Molecular Biology
Michael E O'Donnell, Huilin Li
DNA replication requires separation of genomic duplex DNA strands, an operation that is performed by a hexameric ring-shaped helicase in all domains of life. The structures and chemomechanical actions of these fascinating machines are coming into sharper focus. Although there is no evolutionary relationship between the hexameric helicases of bacteria and those of archaea and eukaryotes, they share many fundamental features. Here we review recent studies of these two groups of hexameric helicases and the unexpected distinctions they have also unveiled...
January 29, 2018: Nature Structural & Molecular Biology
Jonathan A Coleman, Eric Gouaux
Selective serotonin reuptake inhibitors are clinically prescribed antidepressants that act by increasing the local concentrations of neurotransmitters at synapses and in extracellular spaces via blockade of the serotonin transporter. Here we report X-ray structures of engineered thermostable variants of the human serotonin transporter bound to the antidepressants sertraline, fluvoxamine, and paroxetine. The drugs prevent serotonin binding by occupying the central substrate-binding site and stabilizing the transporter in an outward-open conformation...
January 29, 2018: Nature Structural & Molecular Biology
Yunpeng Zhou, John H Bushweller
Membrane oxidoreductase CcdA plays a central role in supplying reducing equivalents from the bacterial cytoplasm to the envelope. It transports electrons across the membrane using a single pair of cysteines by a mechanism that has not yet been elucidated. Here we report an NMR structure of the Thermus thermophilus CcdA (TtCcdA) in an oxidized and outward-facing state. CcdA consists of two inverted structural repeats of three transmembrane helices (2 × 3-TM). We computationally modeled and experimentally validated an inward-facing state, which suggests that CcdA uses an elevator-type movement to shuttle the reactive cysteines across the membrane...
January 29, 2018: Nature Structural & Molecular Biology
Yong Woo Lee, Rajika Arora, Harry Wischnewski, Claus M Azzalin
The shelterin protein TRF2 assembles protective T loops at chromosome ends by stimulating intramolecular invasion of the telomeric G-rich single-stranded DNA (ssDNA) overhang into the duplex telomeric array. The other shelterin factor, TRF1, is thought to mainly facilitate telomeric dsDNA replication without directly participating in end protection. Here we show that in vitro human TRF2 stimulates invasion of G-rich TERRA-like RNA into telomeric dsDNA, leading to formation of telomeric RNA-DNA hybrids (telR loops)...
January 22, 2018: Nature Structural & Molecular Biology
Marcello Clerici, Marco Faini, Lena M Muckenfuss, Ruedi Aebersold, Martin Jinek
Mammalian mRNA biogenesis requires specific recognition of a hexanucleotide AAUAAA motif in the polyadenylation signals (PAS) of precursor mRNA (pre-mRNA) transcripts by the cleavage and polyadenylation specificity factor (CPSF) complex. Here we present a 3.1-Å-resolution cryo-EM structure of a core CPSF module bound to the PAS hexamer motif. The structure reveals the molecular interactions responsible for base-specific recognition, providing a rationale for mechanistic differences between mammalian and yeast 3' polyadenylation...
January 22, 2018: Nature Structural & Molecular Biology
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