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Nature Structural & Molecular Biology

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https://www.readbyqxmd.com/read/28218750/quaternary-contact-in-the-initial-interaction-of-cd4-with-the-hiv-1-envelope-trimer
#1
Qingbo Liu, Priyamvada Acharya, Michael A Dolan, Peng Zhang, Christina Guzzo, Jacky Lu, Alice Kwon, Deepali Gururani, Huiyi Miao, Tatsiana Bylund, Gwo-Yu Chuang, Aliaksandr Druz, Tongqing Zhou, William J Rice, Christoph Wigge, Bridget Carragher, Clinton S Potter, Peter D Kwong, Paolo Lusso
Binding of the gp120 envelope (Env) glycoprotein to the CD4 receptor is the first step in the HIV-1 infectious cycle. Although the CD4-binding site has been extensively characterized, the initial receptor interaction has been difficult to study because of major CD4-induced structural rearrangements. Here we used cryogenic electron microscopy (cryo-EM) to visualize the initial contact of CD4 with the HIV-1 Env trimer at 6.8-Å resolution. A single CD4 molecule is embraced by a quaternary HIV-1-Env surface formed by coalescence of the previously defined CD4-contact region with a second CD4-binding site (CD4-BS2) in the inner domain of a neighboring gp120 protomer...
February 20, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28218749/mechanistic-basis-for-the-recognition-of-a-misfolded-protein-by-the-molecular-chaperone-hsp90
#2
Javier Oroz, Jin Hae Kim, Bliss J Chang, Markus Zweckstetter
The critical toxic species in over 40 human diseases are misfolded proteins. Their interaction with molecular chaperones such as Hsp90, which preferentially interacts with metastable proteins, is essential for the blocking of disease progression. Here we used nuclear magnetic resonance (NMR) spectroscopy to determine the three-dimensional structure of the misfolded cytotoxic monomer of the amyloidogenic human protein transthyretin, which is characterized by the release of the C-terminal β-strand and perturbations of the A-B loop...
February 20, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28218748/hiv-tat-protein-and-amyloid-%C3%AE-peptide-form-multifibrillar-structures-that-cause-neurotoxicity
#3
Alina Hategan, Mario A Bianchet, Joseph Steiner, Elena Karnaukhova, Eliezer Masliah, Adam Fields, Myoung-Hwa Lee, Alex M Dickens, Norman Haughey, Emilios K Dimitriadis, Avindra Nath
Deposition of amyloid-β plaques is increased in the brains of HIV-infected individuals, and the HIV transactivator of transcription (Tat) protein affects amyloidogenesis through several indirect mechanisms. Here, we investigated direct interactions between Tat and amyloid-β peptide. Our in vitro studies showed that in the presence of Tat, uniform amyloid fibrils become double twisted fibrils and further form populations of thick unstructured filaments and aggregates. Specifically, Tat binding to the exterior surfaces of the Aβ fibrils increases β-sheet formation and lateral aggregation into thick multifibrillar structures, thus producing fibers with increased rigidity and mechanical resistance...
February 20, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28218747/mhc-i-peptides-get-out-of-the-groove-and-enable-a-novel-mechanism-of-hiv-1-escape
#4
Phillip Pymm, Patricia T Illing, Sri H Ramarathinam, Geraldine M O'Connor, Victoria A Hughes, Corinne Hitchen, David A Price, Bosco K Ho, Daniel W McVicar, Andrew G Brooks, Anthony W Purcell, Jamie Rossjohn, Julian P Vivian
Major histocompatibility complex class I (MHC-I) molecules play a crucial role in immunity by capturing peptides for presentation to T cells and natural killer (NK) cells. The peptide termini are tethered within the MHC-I antigen-binding groove, but it is unknown whether other presentation modes occur. Here we show that 20% of the HLA-B*57:01 peptide repertoire comprises N-terminally extended sets characterized by a common motif at position 1 (P1) to P2. Structures of HLA-B*57:01 presenting N-terminally extended peptides, including the immunodominant HIV-1 Gag epitope TW10 (TSTLQEQIGW), showed that the N terminus protrudes from the peptide-binding groove...
February 20, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28191894/open-ringed-structure-of-the-cdt1-mcm2-7-complex-as-a-precursor-of-the-mcm-double-hexamer
#5
Yuanliang Zhai, Erchao Cheng, Hao Wu, Ningning Li, Philip Yuk Kwong Yung, Ning Gao, Bik-Kwoon Tye
The minichromosome maintenance complex (MCM) hexameric complex (Mcm2-7) forms the core of the eukaryotic replicative helicase. During G1 phase, two Cdt1-Mcm2-7 heptamers are loaded onto each replication origin by the origin-recognition complex (ORC) and Cdc6 to form an inactive MCM double hexamer (DH), but the detailed loading mechanism remains unclear. Here we examine the structures of the yeast MCM hexamer and Cdt1-MCM heptamer from Saccharomyces cerevisiae. Both complexes form left-handed coil structures with a 10-15-Å gap between Mcm5 and Mcm2, and a central channel that is occluded by the C-terminal domain winged-helix motif of Mcm5...
February 13, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28191893/structural-basis-of-mcm2-7-replicative-helicase-loading-by-orc-cdc6-and-cdt1
#6
Zuanning Yuan, Alberto Riera, Lin Bai, Jingchuan Sun, Saikat Nandi, Christos Spanos, Zhuo Angel Chen, Marta Barbon, Juri Rappsilber, Bruce Stillman, Christian Speck, Huilin Li
To initiate DNA replication, the origin recognition complex (ORC) and Cdc6 load an Mcm2-7 double hexamer onto DNA. Without ATP hydrolysis, ORC-Cdc6 recruits one Cdt1-bound Mcm2-7 hexamer, thus forming an ORC-Cdc6-Cdt1-Mcm2-7 (OCCM) helicase-loading intermediate. Here we report a 3.9-Å structure of Saccharomyces cerevisiae OCCM on DNA. Flexible Mcm2-7 winged-helix domains (WHDs) engage ORC-Cdc6. A three-domain Cdt1 configuration embraces Mcm2, Mcm4, and Mcm6, thus comprising nearly half of the hexamer. The Cdt1 C-terminal domain extends to the Mcm6 WHD, which binds the Orc4 WHD...
February 13, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28191892/mechanism-and-timing-of-mcm2-7-ring-closure-during-dna-replication-origin-licensing
#7
Simina Ticau, Larry J Friedman, Kanokwan Champasa, Ivan R Corrêa, Jeff Gelles, Stephen P Bell
The opening and closing of two ring-shaped Mcm2-7 DNA helicases is necessary to license eukaryotic origins of replication, although the mechanisms controlling these events are unclear. The origin-recognition complex (ORC), Cdc6 and Cdt1 facilitate this process by establishing a topological link between each Mcm2-7 hexamer and origin DNA. Using colocalization single-molecule spectroscopy and single-molecule Förster resonance energy transfer (FRET), we monitored ring opening and closing of Saccharomyces cerevisiae Mcm2-7 during origin licensing...
February 13, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28165511/rdrp-synthesized-antisense-ribosomal-sirnas-silence-pre-rrna-via-the-nuclear-rnai-pathway
#8
Xufei Zhou, Xuezhu Feng, Hui Mao, Mu Li, Fei Xu, Kai Hu, Shouhong Guang
Expression of rRNA affects cell growth and proliferation, but mechanisms that modulate rRNA levels are poorly understood. We conducted a genetic screen for factors that negatively regulate generation of endogenous short interfering RNA (endo-siRNA) in Caenorhabditis elegans and identified a suppressor of siRNA (susi-1) and antisense ribosomal siRNAs (risiRNAs). risiRNAs show sequence complementary to 18S and 26S rRNAs and require RNA-dependent RNA polymerases (RdRPs) for their production. They act through the nuclear RNA interference (RNAi) pathway to downregulate pre-rRNA...
February 6, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28165510/stat2-is-an-essential-adaptor-in-usp18-mediated-suppression-of-type-i-interferon-signaling
#9
Kei-Ichiro Arimoto, Sara Löchte, Samuel A Stoner, Christoph Burkart, Yue Zhang, Sayuri Miyauchi, Stephan Wilmes, Jun-Bao Fan, Jürgen J Heinisch, Zhi Li, Ming Yan, Sandra Pellegrini, Frédéric Colland, Jacob Piehler, Dong-Er Zhang
Type I interferons (IFNs) are multifunctional cytokines that regulate immune responses and cellular functions but also can have detrimental effects on human health. A tight regulatory network therefore controls IFN signaling, which in turn may interfere with medical interventions. The JAK-STAT signaling pathway transmits the IFN extracellular signal to the nucleus, thus resulting in alterations in gene expression. STAT2 is a well-known essential and specific positive effector of type I IFN signaling. Here, we report that STAT2 is also a previously unrecognized, crucial component of the USP18-mediated negative-feedback control in both human and mouse cells...
February 6, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28165509/structural-basis-of-the-specificity-of-usp18-toward-isg15
#10
Anja Basters, Paul P Geurink, Annika Röcker, Katharina F Witting, Roya Tadayon, Sandra Hess, Marta S Semrau, Paola Storici, Huib Ovaa, Klaus-Peter Knobeloch, Günter Fritz
Protein modification by ubiquitin and ubiquitin-like modifiers (Ubls) is counteracted by ubiquitin proteases and Ubl proteases, collectively termed DUBs. In contrast to other proteases of the ubiquitin-specific protease (USP) family, USP18 shows no reactivity toward ubiquitin but specifically deconjugates the interferon-induced Ubl ISG15. To identify the molecular determinants of this specificity, we solved the crystal structures of mouse USP18 alone and in complex with mouse ISG15. USP18 was crystallized in an open and a closed conformation, thus revealing high flexibility of the enzyme...
February 6, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28134932/eukaryotic-rad50-functions-as-a-rod-shaped-dimer
#11
Young Bong Park, Marcel Hohl, Michał Padjasek, Eunyoung Jeong, Kyeong Sik Jin, Artur Krężel, John H J Petrini, Yunje Cho
The Rad50 hook interface is crucial for assembly and various functions of the Mre11 complex. Previous analyses suggested that Rad50 molecules interact within (intracomplex) or between (intercomplex) dimeric complexes. In this study, we determined the structure of the human Rad50 hook and coiled-coil domains. The data suggest that the predominant structure is the intracomplex, in which the two parallel coiled coils proximal to the hook form a rod shape, and that a novel interface within the coiled-coil domains of Rad50 stabilizes the interaction of Rad50 protomers in the dimeric assembly...
January 30, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28134931/g-quadruplex-structures-within-the-3-utr-of-line-1-elements-stimulate-retrotransposition
#12
Aleksandr B Sahakyan, Pierre Murat, Clemens Mayer, Shankar Balasubramanian
Long interspersed nuclear elements (LINEs) are ubiquitous transposable elements in higher eukaryotes that have a significant role in shaping genomes, owing to their abundance. Here we report that guanine-rich sequences in the 3' untranslated regions (UTRs) of hominoid-specific LINE-1 elements are coupled with retrotransposon speciation and contribute to retrotransposition through the formation of G-quadruplex (G4) structures. We demonstrate that stabilization of the G4 motif of a human-specific LINE-1 element by small-molecule ligands stimulates retrotransposition...
January 30, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28134930/xist-dependent-imprinted-x-inactivation-and-the-early-developmental-consequences-of-its-failure
#13
Maud Borensztein, Laurène Syx, Katia Ancelin, Patricia Diabangouaya, Christel Picard, Tao Liu, Jun-Bin Liang, Ivaylo Vassilev, Rafael Galupa, Nicolas Servant, Emmanuel Barillot, Azim Surani, Chong-Jian Chen, Edith Heard
The long noncoding RNA Xist is expressed from only the paternal X chromosome in mouse preimplantation female embryos and mediates transcriptional silencing of that chromosome. In females, absence of Xist leads to postimplantation lethality. Here, through single-cell RNA sequencing of early preimplantation mouse embryos, we found that the initiation of imprinted X-chromosome inactivation absolutely requires Xist. Lack of paternal Xist leads to genome-wide transcriptional misregulation in the early blastocyst and to failure to activate the extraembryonic pathway that is essential for postimplantation development...
January 30, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28134929/the-evolutionary-capacitor-hsp90-buffers-the-regulatory-effects-of-mammalian-endogenous-retroviruses
#14
Barbara Hummel, Erik C Hansen, Aneliya Yoveva, Fernando Aprile-Garcia, Rebecca Hussong, Ritwick Sawarkar
Understanding how genotypes are linked to phenotypes is important in biomedical and evolutionary studies. The chaperone heat-shock protein 90 (HSP90) buffers genetic variation by stabilizing proteins with variant sequences, thereby uncoupling phenotypes from genotypes. Here we report an unexpected role of HSP90 in buffering cis-regulatory variation affecting gene expression. By using the tripartite-motif-containing 28 (TRIM28; also known as KAP1)-mediated epigenetic pathway, HSP90 represses the regulatory influence of endogenous retroviruses (ERVs) on neighboring genes that are critical for mouse development...
January 30, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28112733/site-specific-mapping-of-the-human-sumo-proteome-reveals-co-modification-with-phosphorylation
#15
Ivo A Hendriks, David Lyon, Clifford Young, Lars J Jensen, Alfred C O Vertegaal, Michael L Nielsen
Small ubiquitin-like modifiers (SUMOs) are post-translational modifications (PTMs) that regulate nuclear cellular processes. Here we used an augmented K0-SUMO proteomics strategy to identify 40,765 SUMO acceptor sites and quantify their fractional contribution for 6,747 human proteins. Structural-predictive analyses revealed that lysines residing in disordered regions are preferentially targeted by SUMO, in notable contrast to other widespread lysine modifications. In our data set, we identified 807 SUMOylated peptides that were co-modified by phosphorylation, along with dozens of SUMOylated peptides that were co-modified by ubiquitylation, acetylation and methylation...
January 23, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28112732/structural-snapshot-of-cytoplasmic-pre-60s-ribosomal-particles-bound-by-nmd3-lsg1-tif6-and-reh1
#16
Chengying Ma, Shan Wu, Ningning Li, Yan Chen, Kaige Yan, Zhifei Li, Lvqin Zheng, Jianlin Lei, John L Woolford, Ning Gao
A key step in ribosome biogenesis is the nuclear export of pre-ribosomal particles. Nmd3, a highly conserved protein in eukaryotes, is a specific adaptor required for the export of pre-60S particles. Here we used cryo-electron microscopy (cryo-EM) to characterize Saccharomyces cerevisiae pre-60S particles purified with epitope-tagged Nmd3. Our structural analysis indicates that these particles belong to a specific late stage of cytoplasmic pre-60S maturation in which ribosomal proteins uL16, uL10, uL11, eL40 and eL41 are deficient, but ribosome assembly factors Nmd3, Lsg1, Tif6 and Reh1 are present...
January 23, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28112731/the-gastrula-transition-reorganizes-replication-origin-selection-in-caenorhabditis-elegans
#17
Marta Rodríguez-Martínez, Natalia Pinzón, Charles Ghommidh, Emmanuelle Beyne, Hervé Seitz, Christelle Cayrou, Marcel Méchali
Although some features underlying replication-origin activation in metazoan cells have been determined, little is known about their regulation during metazoan development. Using the nascent-strand purification method, here we identified replication origins throughout Caenorhabditis elegans embryonic development and found that the origin repertoire is thoroughly reorganized after gastrulation onset. During the pluripotent embryonic stages (pregastrula), potential cruciform structures and open chromatin are determining factors that establish replication origins...
January 23, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28112730/cotranslational-folding-of-spectrin-domains-via-partially-structured-states
#18
Ola B Nilsson, Adrian A Nickson, Jeffrey J Hollins, Stephan Wickles, Annette Steward, Roland Beckmann, Gunnar von Heijne, Jane Clarke
How do the key features of protein folding, elucidated from studies on native, isolated proteins, manifest in cotranslational folding on the ribosome? Using a well-characterized family of homologous α-helical proteins with a range of biophysical properties, we show that spectrin domains can fold vectorially on the ribosome and may do so via a pathway different from that of the isolated domain. We use cryo-EM to reveal a folded or partially folded structure, formed in the vestibule of the ribosome. Our results reveal that it is not possible to predict which domains will fold within the ribosome on the basis of the folding behavior of isolated domains; instead, we propose that a complex balance of the rate of folding, the rate of translation and the lifetime of folded or partly folded states will determine whether folding occurs cotranslationally on actively translating ribosomes...
January 23, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28112729/structural-basis-of-dual-ca-2-ph-regulation-of-the-endolysosomal-trpml1-channel
#19
Minghui Li, Wei K Zhang, Nicole M Benvin, Xiaoyuan Zhou, Deyuan Su, Huan Li, Shu Wang, Ioannis E Michailidis, Liang Tong, Xueming Li, Jian Yang
The activities of organellar ion channels are often regulated by Ca(2+) and H(+), which are present in high concentrations in many organelles. Here we report a structural element critical for dual Ca(2+)/pH regulation of TRPML1, a Ca(2+)-release channel crucial for endolysosomal function. TRPML1 mutations cause mucolipidosis type IV (MLIV), a severe lysosomal storage disorder characterized by neurodegeneration, mental retardation and blindness. We obtained crystal structures of the 213-residue luminal domain of human TRPML1 containing three missense MLIV-causing mutations...
January 23, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28092368/molecular-insights-into-lipid-assisted-ca-2-regulation-of-the-trp-channel-polycystin-2
#20
Martin Wilkes, M Gregor Madej, Lydia Kreuter, Daniel Rhinow, Veronika Heinz, Silvia De Sanctis, Sabine Ruppel, Rebecca M Richter, Friederike Joos, Marina Grieben, Ashley C W Pike, Juha T Huiskonen, Elisabeth P Carpenter, Werner Kühlbrandt, Ralph Witzgall, Christine Ziegler
Polycystin-2 (PC2), a calcium-activated cation TRP channel, is involved in diverse Ca(2+) signaling pathways. Malfunctioning Ca(2+) regulation in PC2 causes autosomal-dominant polycystic kidney disease. Here we report two cryo-EM structures of distinct channel states of full-length human PC2 in complex with lipids and cations. The structures reveal conformational differences in the selectivity filter and in the large exoplasmic domain (TOP domain), which displays differing N-glycosylation. The more open structure has one cation bound below the selectivity filter (single-ion mode, PC2SI), whereas multiple cations are bound along the translocation pathway in the second structure (multi-ion mode, PC2MI)...
January 16, 2017: Nature Structural & Molecular Biology
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