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Fusion peptide of HIV-1 as a site of vulnerability to neutralizing antibody.
Kong R, Xu K, Zhou T, Acharya P, Lemmin T, Liu K, Ozorowski G, Soto C, Taft JD, Bailer RT, Cale EM, Chen L, Choi CW, Chuang GY, Doria-Rose NA, Druz A, Georgiev IS, Gorman J, Huang J, Joyce MG, Louder MK, Ma X, McKee K, O'Dell S, Pancera M, Yang Y, Blanchard SC, Mothes W, Burton DR, Koff WC, Connors M, Ward AB, Kwong PD, Mascola JR
(2016) Science 352: 828-33
MeSH Terms: AIDS Vaccines, Amino Acid Sequence, Antibodies, Neutralizing, Antibodies, Viral, B-Lymphocytes, Crystallography, X-Ray, HIV Envelope Protein gp120, HIV Envelope Protein gp41, HIV-1, Humans, Hydrophobic and Hydrophilic Interactions, Immunodominant Epitopes, Molecular Sequence Data, Peptides, Protein Conformation, Viral Fusion Proteins, Virus Internalization
Show Abstract · Added May 3, 2017
The HIV-1 fusion peptide, comprising 15 to 20 hydrophobic residues at the N terminus of the Env-gp41 subunit, is a critical component of the virus-cell entry machinery. Here, we report the identification of a neutralizing antibody, N123-VRC34.01, which targets the fusion peptide and blocks viral entry by inhibiting conformational changes in gp120 and gp41 subunits of Env required for entry. Crystal structures of N123-VRC34.01 liganded to the fusion peptide, and to the full Env trimer, revealed an epitope consisting of the N-terminal eight residues of the gp41 fusion peptide and glycan N88 of gp120, and molecular dynamics showed that the N-terminal portion of the fusion peptide can be solvent-exposed. These results reveal the fusion peptide to be a neutralizing antibody epitope and thus a target for vaccine design.
Copyright © 2016, American Association for the Advancement of Science.
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17 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
Structure and mechanism of the phage T4 recombination mediator protein UvsY.
Gajewski S, Waddell MB, Vaithiyalingam S, Nourse A, Li Z, Woetzel N, Alexander N, Meiler J, White SW
(2016) Proc Natl Acad Sci U S A 113: 3275-80
MeSH Terms: Amino Acid Sequence, Membrane Proteins, Models, Molecular, Molecular Sequence Data, Protein Conformation, Structure-Activity Relationship, Viral Proteins
Show Abstract · Added April 8, 2017
The UvsY recombination mediator protein is critical for efficient homologous recombination in bacteriophage T4 and is the functional analog of the eukaryotic Rad52 protein. During T4 homologous recombination, the UvsX recombinase has to compete with the prebound gp32 single-stranded binding protein for DNA-binding sites and UvsY stimulates this filament nucleation event. We report here the crystal structure of UvsY in four similar open-barrel heptameric assemblies and provide structural and biophysical insights into its function. The UvsY heptamer was confirmed in solution by centrifugation and light scattering, and thermodynamic analyses revealed that the UvsY-ssDNA interaction occurs within the assembly via two distinct binding modes. Using surface plasmon resonance, we also examined the binding of UvsY to both ssDNA and the ssDNA-gp32 complex. These analyses confirmed that ssDNA can bind UvsY and gp32 independently and also as a ternary complex. They also showed that residues located on the rim of the heptamer are required for optimal binding to ssDNA, thus identifying the putative ssDNA-binding surface. We propose a model in which UvsY promotes a helical ssDNA conformation that disfavors the binding of gp32 and initiates the assembly of the ssDNA-UvsX filament.
1 Communities
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7 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
Pathogenic CD4 T cells in type 1 diabetes recognize epitopes formed by peptide fusion.
Delong T, Wiles TA, Baker RL, Bradley B, Barbour G, Reisdorph R, Armstrong M, Powell RL, Reisdorph N, Kumar N, Elso CM, DeNicola M, Bottino R, Powers AC, Harlan DM, Kent SC, Mannering SI, Haskins K
(2016) Science 351: 711-4
MeSH Terms: Amino Acid Sequence, Animals, C-Peptide, CD4-Positive T-Lymphocytes, Clone Cells, Diabetes Mellitus, Experimental, Diabetes Mellitus, Type 1, Epitopes, Immune Tolerance, Insulin-Secreting Cells, Mice, Mice, Inbred NOD, Molecular Sequence Data, Peptides
Show Abstract · Added July 16, 2016
T cell-mediated destruction of insulin-producing β cells in the pancreas causes type 1 diabetes (T1D). CD4 T cell responses play a central role in β cell destruction, but the identity of the epitopes recognized by pathogenic CD4 T cells remains unknown. We found that diabetes-inducing CD4 T cell clones isolated from nonobese diabetic mice recognize epitopes formed by covalent cross-linking of proinsulin peptides to other peptides present in β cell secretory granules. These hybrid insulin peptides (HIPs) are antigenic for CD4 T cells and can be detected by mass spectrometry in β cells. CD4 T cells from the residual pancreatic islets of two organ donors who had T1D also recognize HIPs. Autoreactive T cells targeting hybrid peptides may explain how immune tolerance is broken in T1D.
Copyright © 2016, American Association for the Advancement of Science.
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14 MeSH Terms
A Distributed Network for Social Cognition Enriched for Oxytocin Receptors.
Mitre M, Marlin BJ, Schiavo JK, Morina E, Norden SE, Hackett TA, Aoki CJ, Chao MV, Froemke RC
(2016) J Neurosci 36: 2517-35
MeSH Terms: Amino Acid Sequence, Animals, Auditory Cortex, Cognition, Female, HEK293 Cells, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Molecular Sequence Data, Nerve Net, Receptors, Oxytocin, Social Behavior
Show Abstract · Added April 6, 2017
Oxytocin is a neuropeptide important for social behaviors such as maternal care and parent-infant bonding. It is believed that oxytocin receptor signaling in the brain is critical for these behaviors, but it is unknown precisely when and where oxytocin receptors are expressed or which neural circuits are directly sensitive to oxytocin. To overcome this challenge, we generated specific antibodies to the mouse oxytocin receptor and examined receptor expression throughout the brain. We identified a distributed network of female mouse brain regions for maternal behaviors that are especially enriched for oxytocin receptors, including the piriform cortex, the left auditory cortex, and CA2 of the hippocampus. Electron microscopic analysis of the cerebral cortex revealed that oxytocin receptors were mainly expressed at synapses, as well as on axons and glial processes. Functionally, oxytocin transiently reduced synaptic inhibition in multiple brain regions and enabled long-term synaptic plasticity in the auditory cortex. Thus modulation of inhibition may be a general mechanism by which oxytocin can act throughout the brain to regulate parental behaviors and social cognition.
Copyright © 2016 the authors 0270-6474/16/362517-19$15.00/0.
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15 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
Viral infection causes a shift in the self peptide repertoire presented by human MHC class I molecules.
Spencer CT, Bezbradica JS, Ramos MG, Arico CD, Conant SB, Gilchuk P, Gray JJ, Zheng M, Niu X, Hildebrand W, Link AJ, Joyce S
(2015) Proteomics Clin Appl 9: 1035-52
MeSH Terms: Amino Acid Sequence, Antigen Presentation, Cell Line, Histocompatibility Antigens Class I, Humans, Molecular Sequence Data, Oncogenes, Peptides, Proteomics, Vaccinia virus
Show Abstract · Added February 15, 2016
PURPOSE - MHC class I presentation of peptides allows T cells to survey the cytoplasmic protein milieu of host cells. During infection, presentation of self peptides is, in part, replaced by presentation of microbial peptides. However, little is known about the self peptides presented during infection, despite the fact that microbial infections alter host cell gene expression patterns and protein metabolism.
EXPERIMENTAL DESIGN - The self peptide repertoire presented by HLA-A*01;01, HLA-A*02;01, HLA-B*07;02, HLA-B*35;01, and HLA-B*45;01 (where HLA is human leukocyte antigen) was determined by tandem MS before and after vaccinia virus infection.
RESULTS - We observed a profound alteration in the self peptide repertoire with hundreds of self peptides uniquely presented after infection for which we have coined the term "self peptidome shift." The fraction of novel self peptides presented following infection varied for different HLA class I molecules. A large part (approximately 40%) of the self peptidome shift arose from peptides derived from type I interferon-inducible genes, consistent with cellular responses to viral infection. Interestingly, approximately 12% of self peptides presented after infection showed allelic variation when searched against approximately 300 human genomes.
CONCLUSION AND CLINICAL RELEVANCE - Self peptidome shift in a clinical transplant setting could result in alloreactivity by presenting new self peptides in the context of infection-induced inflammation.
© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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2 Members
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10 MeSH Terms
Characterization of the Domain Orientations of E. coli 5'-Nucleotidase by Fitting an Ensemble of Conformers to DEER Distance Distributions.
Krug U, Alexander NS, Stein RA, Keim A, Mchaourab HS, Sträter N, Meiler J
(2016) Structure 24: 43-56
MeSH Terms: 5'-Nucleotidase, Amino Acid Sequence, Escherichia coli, Escherichia coli Proteins, Molecular Dynamics Simulation, Molecular Sequence Data, Protein Structure, Tertiary
Show Abstract · Added February 5, 2016
Escherichia coli 5'-nucleotidase is a two-domain enzyme exhibiting a unique 96° domain motion that is required for catalysis. Here we present an integrated structural biology study that combines DEER distance distributions with structural information from X-ray crystallography and computational biology to describe the population of presumably almost isoenergetic open and closed states in solution. Ensembles of models that best represent the experimental distance distributions are determined by a Monte Carlo search algorithm. As a result, predominantly open conformations are observed in the unliganded state indicating that the majority of enzyme molecules await substrate binding for the catalytic cycle. The addition of a substrate analog yields ensembles with an almost equal mixture of open and closed states. Thus, in the presence of substrate, efficient catalysis is provided by the simultaneous appearance of open conformers (binding substrate or releasing product) and closed conformers (enabling the turnover of the substrate).
Copyright © 2016 Elsevier Ltd. All rights reserved.
1 Communities
2 Members
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7 MeSH Terms
LMO2 Oncoprotein Stability in T-Cell Leukemia Requires Direct LDB1 Binding.
Layer JH, Alford CE, McDonald WH, Davé UP
(2016) Mol Cell Biol 36: 488-506
MeSH Terms: Adaptor Proteins, Signal Transducing, Amino Acid Sequence, Amino Acid Substitution, Cell Line, DNA-Binding Proteins, Humans, Jurkat Cells, LIM Domain Proteins, Leukemia, T-Cell, Molecular Sequence Data, Mutation, Protein Interaction Domains and Motifs, Protein Interaction Maps, Protein Stability, Proto-Oncogene Proteins, Transcription Factors, Transcriptional Activation
Show Abstract · Added January 26, 2016
LMO2 is a component of multisubunit DNA-binding transcription factor complexes that regulate gene expression in hematopoietic stem and progenitor cell development. Enforced expression of LMO2 causes leukemia by inducing hematopoietic stem cell-like features in T-cell progenitor cells, but the biochemical mechanisms of LMO2 function have not been fully elucidated. In this study, we systematically dissected the LMO2/LDB1-binding interface to investigate the role of this interaction in T-cell leukemia. Alanine scanning mutagenesis of the LIM interaction domain of LDB1 revealed a discrete motif, R(320)LITR, required for LMO2 binding. Most strikingly, coexpression of full-length, wild-type LDB1 increased LMO2 steady-state abundance, whereas coexpression of mutant proteins deficient in LMO2 binding compromised LMO2 stability. These mutant LDB1 proteins also exerted dominant negative effects on growth and transcription in diverse leukemic cell lines. Mass spectrometric analysis of LDB1 binding partners in leukemic lines supports the notion that LMO2/LDB1 function in leukemia occurs in the context of multisubunit complexes, which also protect the LMO2 oncoprotein from degradation. Collectively, these data suggest that the assembly of LMO2 into complexes, via direct LDB1 interaction, is a potential molecular target that could be exploited in LMO2-driven leukemias resistant to existing chemotherapy regimens.
Copyright © 2016, American Society for Microbiology. All Rights Reserved.
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17 MeSH Terms