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Nature Structural & Molecular Biology

Bettina K Zierer, Martin Rübbelke, Franziska Tippel, Tobias Madl, Florian H Schopf, Daniel A Rutz, Klaus Richter, Michael Sattler, Johannes Buchner
Hsp90 couples ATP hydrolysis to large conformational changes essential for activation of client proteins. The structural transitions involve dimerization of the N-terminal domains and formation of 'closed states' involving the N-terminal and middle domains. Here, we used Hsp90 mutants that modulate ATPase activity and biological function as probes to address the importance of conformational cycling for Hsp90 activity. We found no correlation between the speed of ATP turnover and the in vivo activity of Hsp90: some mutants with almost normal ATPase activity were lethal, and some mutants with lower or undetectable ATPase activity were viable...
October 10, 2016: Nature Structural & Molecular Biology
Xudong Chen, Yue Wang, Yu-Zen Chen, Brian L Harry, Akihisa Nakagawa, Eui-Seung Lee, Hongyan Guo, Ding Xue
Caspases are cysteine proteases with critical roles in apoptosis. The Caenorhabditis elegans caspase CED-3 is activated by autocatalytic cleavage, a process enhanced by CED-4. Here we report that the CED-3 zymogen localizes to the perinuclear region in C. elegans germ cells and that CED-3 autocatalytic cleavage is held in check by C. elegans nuclei and activated by CED-4. The nuclear-pore protein NPP-14 interacts with the CED-3 zymogen prodomain, colocalizes with CED-3 in vivo and inhibits CED-3 autoactivation in vitro...
October 10, 2016: Nature Structural & Molecular Biology
Jeffrey S Mugridge, Marcin Ziemniak, Jacek Jemielity, John D Gross
Removal of the 5' cap on mRNA by the decapping enzyme Dcp2 is a critical step in 5'-to-3' mRNA decay. Understanding the structural basis of Dcp2 activity has been a challenge because Dcp2 is dynamic and has weak affinity for the cap substrate. Here we present a 2.6-Å-resolution crystal structure of a heterotrimer of fission yeast Dcp2, its essential activator Dcp1, and the human NMD cofactor PNRC2, in complex with a tight-binding cap analog. Cap binding is accompanied by a conformational change in Dcp2, thereby forming a composite nucleotide-binding site comprising conserved residues in the catalytic and regulatory domains...
October 3, 2016: Nature Structural & Molecular Biology
Clément Charenton, Valerio Taverniti, Claudine Gaudon-Plesse, Régis Back, Bertrand Séraphin, Marc Graille
Elimination of the 5' cap of eukaryotic mRNAs, known as decapping, is considered to be a crucial, irreversible and highly regulated step required for the rapid degradation of mRNA by Xrn1, the major cytoplasmic 5'-3' exonuclease. Decapping is accomplished by the recruitment of a protein complex formed by the Dcp2 catalytic subunit and its Dcp1 cofactor. However, this complex has a low intrinsic enzymatic activity and requires several accessory proteins such as the Lsm1-7 complex, Pat1, Edc1-Edc2 and/or Edc3 to be fully active...
October 3, 2016: Nature Structural & Molecular Biology
Shanshan Hu, Xiaolin Wang, Ge Shan
Noncoding RNAs, mobile elements, and alternative splicing are all critical for the regulation of gene expression. Here we show that a conserved noncoding RNA acquires a new function due to the insertion of a mobile element. We identified a noncoding RNA, termed 5S-OT, which is transcribed from 5S rDNA loci in eukaryotes including fission yeast and mammals. 5S-OT plays a cis role in regulating the transcription of 5S rRNA in mice and humans. In the anthropoidea suborder of primates, an antisense Alu element has been inserted at the 5S-OT locus...
October 3, 2016: Nature Structural & Molecular Biology
Piere Rodriguez-Aliaga, Luis Ramirez, Frank Kim, Carlos Bustamante, Andreas Martin
ATP-dependent proteases of the AAA+ family, including Escherichia coli ClpXP and the eukaryotic proteasome, contribute to maintenance of cellular proteostasis. ClpXP unfolds and translocates substrates into an internal degradation chamber, using cycles of alternating dwell and burst phases. The ClpX motor performs chemical transformations during the dwell and translocates the substrate in increments of 1-4 nm during the burst, but the processes occurring during these phases remain unknown. Here we characterized the complete mechanochemical cycle of ClpXP, showing that ADP release and ATP binding occur nonsequentially during the dwell, whereas ATP hydrolysis and phosphate release occur during the burst...
September 26, 2016: Nature Structural & Molecular Biology
Baptiste Fischer, Kevin Lüthy, Jone Paesmans, Charlotte De Koninck, Ine Maes, Jef Swerts, Sabine Kuenen, Valerie Uytterhoeven, Patrik Verstreken, Wim Versées
Mutations in TBC1D24 cause severe epilepsy and DOORS syndrome, but the molecular mechanisms underlying these pathologies are unresolved. We solved the crystal structure of the TBC domain of the Drosophila ortholog Skywalker, revealing an unanticipated cationic pocket conserved among TBC1D24 homologs. Cocrystallization and biochemistry showed that this pocket binds phosphoinositides phosphorylated at the 4 and 5 positions. The most prevalent patient mutations affect the phosphoinositide-binding pocket and inhibit lipid binding...
September 26, 2016: Nature Structural & Molecular Biology
Leena Ackermann, Michael Schell, Wojciech Pokrzywa, Éva Kevei, Anton Gartner, Björn Schumacher, Thorsten Hoppe
Multiple protein ubiquitination events at DNA double-strand breaks (DSBs) regulate damage recognition, signaling and repair. It has remained poorly understood how the repair process of DSBs is coordinated with the apoptotic response. Here, we identified the E4 ubiquitin ligase UFD-2 as a mediator of DNA-damage-induced apoptosis in a genetic screen in Caenorhabditis elegans. We found that, after initiation of homologous recombination by RAD-51, UFD-2 forms foci that contain substrate-processivity factors including the ubiquitin-selective segregase CDC-48 (p97), the deubiquitination enzyme ATX-3 (Ataxin-3) and the proteasome...
September 26, 2016: Nature Structural & Molecular Biology
Kanghyun Lee, Ruchika Sharma, Om Kumar Shrestha, Craig A Bingman, Elizabeth A Craig
Ribosome-associated J protein-Hsp70 chaperones promote nascent-polypeptide folding and normal translational fidelity. The J protein Zuo1 is known to span the ribosomal subunits, but understanding of its function is limited. Here we present new structural and cross-linking data allowing more precise positioning of Saccharomyces cerevisiae Zuo1 near the 60S polypeptide-exit site and suggesting interactions of Zuo1 with the ribosomal protein eL31 and 25S rRNA helix 24. The junction between the 60S-interacting and subunit-spanning helices is a hinge that positions Zuo1 on the 40S yet accommodates subunit rotation...
September 26, 2016: Nature Structural & Molecular Biology
Joshua P Ramsay
No abstract text is available yet for this article.
October 5, 2016: Nature Structural & Molecular Biology
Pierre De Meyts
No abstract text is available yet for this article.
October 5, 2016: Nature Structural & Molecular Biology
(no author information available yet)
No abstract text is available yet for this article.
October 5, 2016: Nature Structural & Molecular Biology
Harry B Gristick, Lotta von Boehmer, Anthony P West, Michael Schamber, Anna Gazumyan, Jovana Golijanin, Michael S Seaman, Gerd Fätkenheuer, Florian Klein, Michel C Nussenzweig, Pamela J Bjorkman
HIV-1 vaccine design is informed by structural studies elucidating mechanisms by which broadly neutralizing antibodies (bNAbs) recognize and/or accommodate N-glycans on the trimeric envelope glycoprotein (Env). Variability in high-mannose and complex-type Env glycoforms leads to heterogeneity that usually precludes visualization of the native glycan shield. We present 3.5-Å- and 3.9-Å-resolution crystal structures of the HIV-1 Env trimer with fully processed and native glycosylation, revealing a glycan shield of high-mannose and complex-type N-glycans, which we used to define complete epitopes of two bNAbs...
October 2016: Nature Structural & Molecular Biology
Alexandra C Walls, M Alejandra Tortorici, Brandon Frenz, Joost Snijder, Wentao Li, Félix A Rey, Frank DiMaio, Berend-Jan Bosch, David Veesler
The threat of a major coronavirus pandemic urges the development of strategies to combat these pathogens. Human coronavirus NL63 (HCoV-NL63) is an α-coronavirus that can cause severe lower-respiratory-tract infections requiring hospitalization. We report here the 3.4-Å-resolution cryo-EM reconstruction of the HCoV-NL63 coronavirus spike glycoprotein trimer, which mediates entry into host cells and is the main target of neutralizing antibodies during infection. The map resolves the extensive glycan shield obstructing the protein surface and, in combination with mass spectrometry, provides a structural framework to understand the accessibility to antibodies...
October 2016: Nature Structural & Molecular Biology
John G Menting, Joanna Gajewiak, Christopher A MacRaild, Danny Hung-Chieh Chou, Maria M Disotuar, Nicholas A Smith, Charleen Miller, Judit Erchegyi, Jean E Rivier, Baldomero M Olivera, Briony E Forbes, Brian J Smith, Raymond S Norton, Helena Safavi-Hemami, Michael C Lawrence
Insulins in the venom of certain fish-hunting cone snails facilitate prey capture by rapidly inducing hypoglycemic shock. One such insulin, Conus geographus G1 (Con-Ins G1), is the smallest known insulin found in nature and lacks the C-terminal segment of the B chain that, in human insulin, mediates engagement of the insulin receptor and assembly of the hormone's hexameric storage form. Removal of this segment (residues B23-B30) in human insulin results in substantial loss of receptor affinity. Here, we found that Con-Ins G1 is monomeric, strongly binds the human insulin receptor and activates receptor signaling...
October 2016: Nature Structural & Molecular Biology
Thomas Clairfeuille, Caroline Mas, Audrey S M Chan, Zhe Yang, Maria Tello-Lafoz, Mintu Chandra, Jocelyn Widagdo, Markus C Kerr, Blessy Paul, Isabel Mérida, Rohan D Teasdale, Nathan J Pavlos, Victor Anggono, Brett M Collins
Recycling of internalized receptors from endosomal compartments is essential for the receptors' cell-surface homeostasis. Sorting nexin 27 (SNX27) cooperates with the retromer complex in the recycling of proteins containing type I PSD95-Dlg-ZO1 (PDZ)-binding motifs. Here we define specific acidic amino acid sequences upstream of the PDZ-binding motif required for high-affinity engagement of the human SNX27 PDZ domain. However, a subset of SNX27 ligands, such as the β2 adrenergic receptor and N-methyl-D-aspartate (NMDA) receptor, lack these sequence determinants...
October 2016: Nature Structural & Molecular Biology
Addison V Wright, Jennifer A Doudna
Bacterial CRISPR-Cas systems include genomic arrays of short repeats flanking foreign DNA sequences and provide adaptive immunity against viruses. Integration of foreign DNA must occur specifically to avoid damaging the genome or the CRISPR array, but surprisingly promiscuous activity occurs in vitro. Here we reconstituted full-site DNA integration and show that the Streptococcus pyogenes type II-A Cas1-Cas2 integrase maintains specificity in part through limitations on the second integration step. At non-CRISPR sites, integration stalls at the half-site intermediate, thereby enabling reaction reversal...
October 2016: Nature Structural & Molecular Biology
Ying Wu, Xiaohong Zhou, Christopher O Barnes, Maria DeLucia, Aina E Cohen, Angela M Gronenborn, Jinwoo Ahn, Guillermo Calero
The HIV-1 accessory protein Vpr is required for efficient viral infection of macrophages and promotion of viral replication in T cells. Vpr's biological activities are closely linked to the interaction with human DCAF1, a cellular substrate receptor of the Cullin4-RING E3 ubiquitin ligase (CRL4) of the host ubiquitin-proteasome-mediated protein degradation pathway. The molecular details of how Vpr usurps the protein degradation pathway have not been delineated. Here we present the crystal structure of the DDB1-DCAF1-HIV-1-Vpr-uracil-DNA glycosylase (UNG2) complex...
October 2016: Nature Structural & Molecular Biology
Christos Gatsogiannis, Felipe Merino, Daniel Prumbaum, Daniel Roderer, Franziska Leidreiter, Dominic Meusch, Stefan Raunser
Tc toxins from pathogenic bacteria use a special syringe-like mechanism to perforate the host cell membrane and inject a deadly enzyme into the host cytosol. The molecular mechanism of this unusual injection system is poorly understood. Using electron cryomicroscopy, we determined the structure of TcdA1 from Photorhabdus luminescens embedded in lipid nanodiscs. In our structure, compared with the previous structure of TcdA1 in the prepore state, the transmembrane helices rearrange in the membrane and open the initially closed pore...
October 2016: Nature Structural & Molecular Biology
Ignacio Mir-Sanchis, Christina A Roman, Agnieszka Misiura, Ying Z Pigli, Susan Boyle-Vavra, Phoebe A Rice
Methicillin-resistant Staphylococcus aureus (MRSA) is a public-health threat worldwide. Although the mobile genomic island responsible for this phenotype, staphylococcal cassette chromosome (SCC), has been thought to be nonreplicative, we predicted DNA-replication-related functions for some of the conserved proteins encoded by SCC. We show that one of these, Cch, is homologous to the self-loading initiator helicases of an unrelated family of genomic islands, that it is an active 3'-to-5' helicase and that the adjacent ORF encodes a single-stranded DNA-binding protein...
October 2016: Nature Structural & Molecular Biology
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