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HCV Broadly Neutralizing Antibodies Use a CDRH3 Disulfide Motif to Recognize an E2 Glycoprotein Site that Can Be Targeted for Vaccine Design.
Flyak AI, Ruiz S, Colbert MD, Luong T, Crowe JE, Bailey JR, Bjorkman PJ
(2018) Cell Host Microbe 24: 703-716.e3
MeSH Terms: Antibodies, Neutralizing, Antibodies, Viral, Binding Sites, Disulfides, Drug Design, Epitopes, Hepacivirus, Hepatitis C, Hepatitis C Antibodies, Humans, Immunoglobulin G, Models, Molecular, Protein Conformation, Sequence Alignment, Viral Envelope Proteins, Viral Hepatitis Vaccines, X-Ray Diffraction
Show Abstract · Added March 31, 2019
Hepatitis C virus (HCV) vaccine efforts are hampered by the extensive genetic diversity of HCV envelope glycoproteins E1 and E2. Structures of broadly neutralizing antibodies (bNAbs) (e.g., HEPC3, HEPC74) isolated from individuals who spontaneously cleared HCV infection facilitate immunogen design to elicit antibodies against multiple HCV variants. However, challenges in expressing HCV glycoproteins previously limited bNAb-HCV structures to complexes with truncated E2 cores. Here we describe crystal structures of full-length E2 ectodomain complexes with HEPC3 and HEPC74, revealing lock-and-key antibody-antigen interactions, E2 regions (including a target of immunogen design) that were truncated or disordered in E2 cores, and an antibody CDRH3 disulfide motif that exhibits common interactions with a conserved epitope despite different bNAb-E2 binding orientations. The structures display unusual features relevant to common genetic signatures of HCV bNAbs and demonstrate extraordinary plasticity in antibody-antigen interactions. In addition, E2 variants that bind HEPC3/HEPC74-like germline precursors may represent candidate vaccine immunogens.
Copyright © 2018 Elsevier Inc. All rights reserved.
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17 MeSH Terms
Broadly neutralizing antibodies targeting the HIV-1 envelope V2 apex confer protection against a clade C SHIV challenge.
Julg B, Tartaglia LJ, Keele BF, Wagh K, Pegu A, Sok D, Abbink P, Schmidt SD, Wang K, Chen X, Joyce MG, Georgiev IS, Choe M, Kwong PD, Doria-Rose NA, Le K, Louder MK, Bailer RT, Moore PL, Korber B, Seaman MS, Abdool Karim SS, Morris L, Koup RA, Mascola JR, Burton DR, Barouch DH
(2017) Sci Transl Med 9:
MeSH Terms: Amino Acid Sequence, Animals, Antibodies, Neutralizing, CD4-Positive T-Lymphocytes, Female, HIV Envelope Protein gp120, HIV-1, Macaca mulatta, Male, Neutralization Tests, Sequence Alignment, Simian Acquired Immunodeficiency Syndrome, Simian Immunodeficiency Virus, Viral Load
Show Abstract · Added March 14, 2018
Neutralizing antibodies to the V2 apex antigenic region of the HIV-1 envelope (Env) trimer are among the most prevalent cross-reactive antibodies elicited by natural infection. Two recently described V2-specific antibodies, PGDM1400 and CAP256-VRC26.25, have demonstrated exquisite potency and neutralization breadth against HIV-1. However, little data exist on the protective efficacy of V2-specific neutralizing antibodies. We created a novel SHIV-325c viral stock that included a clade C HIV-1 envelope and was susceptible to neutralization by both of these antibodies. Rhesus macaques received a single infusion of either antibody at three different concentrations (2, 0.4, and 0.08 mg/kg) before challenge with SHIV-325c. PGDM1400 was fully protective at the 0.4 mg/kg dose, whereas CAP256-VRC26.25-LS was fully protective even at the 0.08 mg/kg dose, which correlated with its greater in vitro neutralization potency against the challenge virus. Serum antibody concentrations required for protection were <0.75 μg/ml for CAP256-VRC26.25-LS. These data demonstrate unprecedented potency and protective efficacy of V2-specific neutralizing antibodies in nonhuman primates and validate V2 as a potential target for the prevention of HIV-1 infection in passive immunization strategies in humans.
Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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14 MeSH Terms
Identification of Phosphorylation Codes for Arrestin Recruitment by G Protein-Coupled Receptors.
Zhou XE, He Y, de Waal PW, Gao X, Kang Y, Van Eps N, Yin Y, Pal K, Goswami D, White TA, Barty A, Latorraca NR, Chapman HN, Hubbell WL, Dror RO, Stevens RC, Cherezov V, Gurevich VV, Griffin PR, Ernst OP, Melcher K, Xu HE
(2017) Cell 170: 457-469.e13
MeSH Terms: Amino Acid Sequence, Animals, Arrestins, Chromatography, Liquid, Humans, Mice, Models, Molecular, Phosphorylation, Rats, Rhodopsin, Sequence Alignment, Tandem Mass Spectrometry, X-Rays
Show Abstract · Added March 14, 2018
G protein-coupled receptors (GPCRs) mediate diverse signaling in part through interaction with arrestins, whose binding promotes receptor internalization and signaling through G protein-independent pathways. High-affinity arrestin binding requires receptor phosphorylation, often at the receptor's C-terminal tail. Here, we report an X-ray free electron laser (XFEL) crystal structure of the rhodopsin-arrestin complex, in which the phosphorylated C terminus of rhodopsin forms an extended intermolecular β sheet with the N-terminal β strands of arrestin. Phosphorylation was detected at rhodopsin C-terminal tail residues T336 and S338. These two phospho-residues, together with E341, form an extensive network of electrostatic interactions with three positively charged pockets in arrestin in a mode that resembles binding of the phosphorylated vasopressin-2 receptor tail to β-arrestin-1. Based on these observations, we derived and validated a set of phosphorylation codes that serve as a common mechanism for phosphorylation-dependent recruitment of arrestins by GPCRs.
Copyright © 2017 Elsevier Inc. All rights reserved.
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13 MeSH Terms
C-terminal motif of human neuropeptide Y receptor determines internalization and arrestin recruitment.
Wanka L, Babilon S, Burkert K, Mörl K, Gurevich VV, Beck-Sickinger AG
(2017) Cell Signal 29: 233-239
MeSH Terms: Amino Acid Motifs, Amino Acid Sequence, Amino Acids, Animals, COS Cells, Cercopithecus aethiops, Endocytosis, HEK293 Cells, Humans, Mutant Proteins, Receptors, Neuropeptide Y, Reproducibility of Results, Sequence Alignment, Sequence Deletion, Structure-Activity Relationship, beta-Arrestin 2
Show Abstract · Added March 14, 2018
The human neuropeptide Y receptor is a rhodopsin-like G protein-coupled receptor (GPCR), which contributes to anorexigenic signals. Thus, this receptor is a highly interesting target for metabolic diseases. As GPCR internalization and trafficking affect receptor signaling and vice versa, we aimed to investigate the molecular mechanism of hYR desensitization and endocytosis. The role of distinct segments of the hYR carboxyl terminus was investigated by fluorescence microscopy, binding assays, inositol turnover experiments and bioluminescence resonance energy transfer assays to examine the internalization behavior of hYR and its interaction with arrestin-3. Based on results of C-terminal deletion mutants and substitution of single amino acids, the motif EESEHLPLSTVHTEVSKGS was identified, with glutamate, threonine and serine residues playing key roles, based on site-directed mutagenesis. Thus, we identified the internalization motif for the human neuropeptide Y receptor, which regulates arrestin-3 recruitment and receptor endocytosis.
Copyright © 2016 Elsevier Inc. All rights reserved.
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16 MeSH Terms
Structures of Ebola virus GP and sGP in complex with therapeutic antibodies.
Pallesen J, Murin CD, de Val N, Cottrell CA, Hastie KM, Turner HL, Fusco ML, Flyak AI, Zeitlin L, Crowe JE, Andersen KG, Saphire EO, Ward AB
(2016) Nat Microbiol 1: 16128
MeSH Terms: Amino Acid Sequence, Antibodies, Monoclonal, Antibody Formation, Cross Reactions, Cryoelectron Microscopy, Ebolavirus, Epitopes, Glycoproteins, Hemorrhagic Fever, Ebola, Humans, Membrane Glycoproteins, Models, Structural, Mutation, Protein Multimerization, Sequence Alignment, Viral Proteins
Show Abstract · Added April 13, 2017
The Ebola virus (EBOV) GP gene encodes two glycoproteins. The major product is a soluble, dimeric glycoprotein (sGP) that is secreted abundantly. Despite the abundance of sGP during infection, little is known regarding its structure or functional role. A minor product, resulting from transcriptional editing, is the transmembrane-anchored, trimeric viral surface glycoprotein (GP). GP mediates attachment to and entry into host cells, and is the intended target of antibody therapeutics. Because large portions of sequence are shared between GP and sGP, it has been hypothesized that sGP may potentially subvert the immune response or may contribute to pathogenicity. In this study, we present cryo-electron microscopy structures of GP and sGP in complex with GP-specific and GP/sGP cross-reactive antibodies undergoing human clinical trials. The structure of the sGP dimer presented here, in complex with both an sGP-specific antibody and a GP/sGP cross-reactive antibody, permits us to unambiguously assign the oligomeric arrangement of sGP and compare its structure and epitope presentation to those of GP. We also provide biophysical evaluation of naturally occurring GP/sGP mutations that fall within the footprints identified by our high-resolution structures. Taken together, our data provide a detailed and more complete picture of the accessible Ebolavirus glycoprotein landscape and a structural basis to evaluate patient and vaccine antibody responses towards differently structured products of the GP gene.
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16 MeSH Terms
A Genome-Scale Investigation of How Sequence, Function, and Tree-Based Gene Properties Influence Phylogenetic Inference.
Shen XX, Salichos L, Rokas A
(2016) Genome Biol Evol 8: 2565-80
MeSH Terms: Animals, Base Composition, Genome, Fungal, Mammals, Phylogeny, Sequence Alignment, Yeasts
Show Abstract · Added April 6, 2017
Molecular phylogenetic inference is inherently dependent on choices in both methodology and data. Many insightful studies have shown how choices in methodology, such as the model of sequence evolution or optimality criterion used, can strongly influence inference. In contrast, much less is known about the impact of choices in the properties of the data, typically genes, on phylogenetic inference. We investigated the relationships between 52 gene properties (24 sequence-based, 19 function-based, and 9 tree-based) with each other and with three measures of phylogenetic signal in two assembled data sets of 2,832 yeast and 2,002 mammalian genes. We found that most gene properties, such as evolutionary rate (measured through the percent average of pairwise identity across taxa) and total tree length, were highly correlated with each other. Similarly, several gene properties, such as gene alignment length, Guanine-Cytosine content, and the proportion of tree distance on internal branches divided by relative composition variability (treeness/RCV), were strongly correlated with phylogenetic signal. Analysis of partial correlations between gene properties and phylogenetic signal in which gene evolutionary rate and alignment length were simultaneously controlled, showed similar patterns of correlations, albeit weaker in strength. Examination of the relative importance of each gene property on phylogenetic signal identified gene alignment length, alongside with number of parsimony-informative sites and variable sites, as the most important predictors. Interestingly, the subsets of gene properties that optimally predicted phylogenetic signal differed considerably across our three phylogenetic measures and two data sets; however, gene alignment length and RCV were consistently included as predictors of all three phylogenetic measures in both yeasts and mammals. These results suggest that a handful of sequence-based gene properties are reliable predictors of phylogenetic signal and could be useful in guiding the choice of phylogenetic markers.
© The Author 2016. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.
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7 MeSH Terms
Wnt pathway activation by ADP-ribosylation.
Yang E, Tacchelly-Benites O, Wang Z, Randall MP, Tian A, Benchabane H, Freemantle S, Pikielny C, Tolwinski NS, Lee E, Ahmed Y
(2016) Nat Commun 7: 11430
MeSH Terms: Adenosine Diphosphate Ribose, Amino Acid Sequence, Animals, Animals, Genetically Modified, Axin Protein, Cell Line, Tumor, Drosophila Proteins, Drosophila melanogaster, Embryo, Nonmammalian, Gene Expression Regulation, Developmental, HEK293 Cells, Humans, Low Density Lipoprotein Receptor-Related Protein-6, Lymphocytes, Molecular Sequence Data, Proteolysis, Sequence Alignment, Tankyrases, Wnt Signaling Pathway, Wnt3A Protein, beta Catenin
Show Abstract · Added February 13, 2017
Wnt/β-catenin signalling directs fundamental processes during metazoan development and can be aberrantly activated in cancer. Wnt stimulation induces the recruitment of the scaffold protein Axin from an inhibitory destruction complex to a stimulatory signalosome. Here we analyse the early effects of Wnt on Axin and find that the ADP-ribose polymerase Tankyrase (Tnks)--known to target Axin for proteolysis-regulates Axin's rapid transition following Wnt stimulation. We demonstrate that the pool of ADP-ribosylated Axin, which is degraded under basal conditions, increases immediately following Wnt stimulation in both Drosophila and human cells. ADP-ribosylation of Axin enhances its interaction with the Wnt co-receptor LRP6, an essential step in signalosome assembly. We suggest that in addition to controlling Axin levels, Tnks-dependent ADP-ribosylation promotes the reprogramming of Axin following Wnt stimulation; and propose that Tnks inhibition blocks Wnt signalling not only by increasing destruction complex activity, but also by impeding signalosome assembly.
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21 MeSH Terms
Maturation Pathway from Germline to Broad HIV-1 Neutralizer of a CD4-Mimic Antibody.
Bonsignori M, Zhou T, Sheng Z, Chen L, Gao F, Joyce MG, Ozorowski G, Chuang GY, Schramm CA, Wiehe K, Alam SM, Bradley T, Gladden MA, Hwang KK, Iyengar S, Kumar A, Lu X, Luo K, Mangiapani MC, Parks RJ, Song H, Acharya P, Bailer RT, Cao A, Druz A, Georgiev IS, Kwon YD, Louder MK, Zhang B, Zheng A, Hill BJ, Kong R, Soto C, NISC Comparative Sequencing Program, Mullikin JC, Douek DC, Montefiori DC, Moody MA, Shaw GM, Hahn BH, Kelsoe G, Hraber PT, Korber BT, Boyd SD, Fire AZ, Kepler TB, Shapiro L, Ward AB, Mascola JR, Liao HX, Kwong PD, Haynes BF
(2016) Cell 165: 449-63
MeSH Terms: AIDS Vaccines, Amino Acid Sequence, Antibodies, Neutralizing, B-Lymphocytes, HIV Antibodies, HIV Envelope Protein gp120, HIV Infections, HIV-1, Humans, Models, Molecular, Molecular Sequence Data, Sequence Alignment
Show Abstract · Added May 3, 2017
Antibodies with ontogenies from VH1-2 or VH1-46-germline genes dominate the broadly neutralizing response against the CD4-binding site (CD4bs) on HIV-1. Here, we define with longitudinal sampling from time-of-infection the development of a VH1-46-derived antibody lineage that matured to neutralize 90% of HIV-1 isolates. Structures of lineage antibodies CH235 (week 41 from time-of-infection, 18% breadth), CH235.9 (week 152, 77%), and CH235.12 (week 323, 90%) demonstrated the maturing epitope to focus on the conformationally invariant portion of the CD4bs. Similarities between CH235 lineage and five unrelated CD4bs lineages in epitope focusing, length-of-time to develop breadth, and extraordinary level of somatic hypermutation suggested commonalities in maturation among all CD4bs antibodies. Fortunately, the required CH235-lineage hypermutation appeared substantially guided by the intrinsic mutability of the VH1-46 gene, which closely resembled VH1-2. We integrated our CH235-lineage findings with a second broadly neutralizing lineage and HIV-1 co-evolution to suggest a vaccination strategy for inducing both lineages.
Copyright © 2016 Elsevier Inc. All rights reserved.
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12 MeSH Terms
Identification of a Substrate Recognition Domain in the Replication Stress Response Protein Zinc Finger Ran-binding Domain-containing Protein 3 (ZRANB3).
Badu-Nkansah A, Mason AC, Eichman BF, Cortez D
(2016) J Biol Chem 291: 8251-7
MeSH Terms: Adenosine Triphosphate, Amino Acid Sequence, Animals, DNA, DNA Damage, DNA Helicases, DNA Repair, HEK293 Cells, Humans, Mice, Molecular Sequence Data, Protein Structure, Tertiary, Sequence Alignment
Show Abstract · Added April 7, 2017
DNA damage and other forms of replication stress can cause replication forks to stall. Replication stress response proteins stabilize and resolve stalled forks by mechanisms that include fork remodeling to facilitate repair or bypass of damaged templates. Several enzymes including SMARCAL1, HLTF, and ZRANB3 catalyze these reactions. SMARCAL1 and HLTF utilize structurally distinct accessory domains attached to an ATPase motor domain to facilitate DNA binding and catalysis of fork remodeling reactions. Here we describe a substrate recognition domain within ZRANB3 that is needed for it to recognize forked DNA structures, hydrolyze ATP, catalyze fork remodeling, and act as a structure-specific endonuclease. Thus, substrate recognition domains are a common feature of fork remodeling, SNF2-family, DNA-dependent ATPases, and our study provides further mechanistic understanding of how these enzymes maintain genome integrity during DNA replication.
© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.
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13 MeSH Terms
Broadly Neutralizing Alphavirus Antibodies Bind an Epitope on E2 and Inhibit Entry and Egress.
Fox JM, Long F, Edeling MA, Lin H, van Duijl-Richter MKS, Fong RH, Kahle KM, Smit JM, Jin J, Simmons G, Doranz BJ, Crowe JE, Fremont DH, Rossmann MG, Diamond MS
(2015) Cell 163: 1095-1107
MeSH Terms: Alphavirus, Alphavirus Infections, Amino Acid Sequence, Animals, Antibodies, Monoclonal, Antibodies, Neutralizing, Antibodies, Viral, Chikungunya virus, Cryoelectron Microscopy, Epitopes, Glycoproteins, Humans, Immunoglobulin Fab Fragments, Mice, Models, Molecular, Molecular Sequence Data, Protein Structure, Tertiary, Sequence Alignment, Viral Envelope Proteins, Viral Vaccines, Virus Internalization
Show Abstract · Added January 26, 2016
We screened a panel of mouse and human monoclonal antibodies (MAbs) against chikungunya virus and identified several with inhibitory activity against multiple alphaviruses. Passive transfer of broadly neutralizing MAbs protected mice against infection by chikungunya, Mayaro, and O'nyong'nyong alphaviruses. Using alanine-scanning mutagenesis, loss-of-function recombinant proteins and viruses, and multiple functional assays, we determined that broadly neutralizing MAbs block multiple steps in the viral lifecycle, including entry and egress, and bind to a conserved epitope on the B domain of the E2 glycoprotein. A 16 Å resolution cryo-electron microscopy structure of a Fab fragment bound to CHIKV E2 B domain provided an explanation for its neutralizing activity. Binding to the B domain was associated with repositioning of the A domain of E2 that enabled cross-linking of neighboring spikes. Our results suggest that B domain antigenic determinants could be targeted for vaccine or antibody therapeutic development against multiple alphaviruses of global concern.
Copyright © 2015 Elsevier Inc. All rights reserved.
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21 MeSH Terms