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Understanding the health effects of disasters is critical for effective preparedness, response, recovery, and mitigation. However, research is negatively impacted by both the limited availability of disaster data and the difficulty of identifying and utilizing disaster-specific and health data sources relevant to disaster research and management. In response to numerous requests from disaster researchers, emergency managers, and operational response organizations, 73 distinct data sources at the intersection of disasters and health were compiled and categorized. These data sources generally cover the entire United States, address both disasters and health, and are available to researchers at little or no cost. Data sources are described and characterized to support improved research and guide evidence-based decision making. Current gaps and potential solutions are presented to improve disaster data collection, utilization, and dissemination.
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The Department of Homeland Security's (DHS) Science and Technology (S&T) Directorate plays a role in public health that extends beyond biodefense. These responsibilities were exercised as part of the 2014-16 Ebola outbreak, leading to productive and beneficial contributions to the international public health response and improved operations in the United States. However, we and others have identified numerous areas for improvement. Based on our successes and lessons learned, we propose a number of ways that DHS, the interagency, and academia can act now to ensure improved responses to future public health crises. These include pre-developing scientific capabilities to respond agnostically to threats, and disease-specific master question lists to organize and inform initial efforts. We are generating DHS-specific playbooks and tools for anticipating future needs and capturing requests from DHS components and our national and international partners, where efforts will also be used to refine and exercise communication and information-sharing practices. These experiences and improvement efforts have encouraged discussions on the role of science in developing government policy, specifically responding to public health crises. We propose specific considerations for both scientists and government decision makers to ensure that the best available science is incorporated into policy and operational decisions to facilitate highly effective responses to future health crises.
Assuntos
Planejamento em Desastres , Surtos de Doenças/prevenção & controle , Disseminação de Informação/métodos , Comunicação , Doença pelo Vírus Ebola/prevenção & controle , Humanos , Formulação de Políticas , Administração em Saúde Pública , Estados UnidosRESUMO
Biological threats consist of traditional, emerging, enhanced, and advanced threats, but current biodefense approaches focus almost entirely on a subset of traditional threats. There is an urgent need to develop a comprehensive, rational, and systematic plan to address and mitigate the broader risk space. Myriad possible strategies exist, but an ideal strategy will extend beyond a list of agents. This article proposes a functionality-based approach based on systematic identification of key functional elements, essentially focusing on mechanisms of what constitutes a threat: The key threat element is addressed directly instead of extensive characterization of ancillary details. Examples might include a potent toxin, long-term environmental stability, or a specific protein causing morbidity/mortality. By identifying the critical components leading to disease, limited time, efforts, and resources can be focused to address the greatest risks. Further, as future threats will likely contain critical aspects of known agents, this approach will potentially address a large area of uncharacterized risk space. Thus, focused research can buy down a large area of risk space while still addressing traditional threats and mission needs. Application of this strategy will move the field away from agent-based lists toward a more comprehensive hazard analysis and will position biodefense and health communities to prepare for the threats of the future.
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Bioterrorismo , Exposição Ambiental/prevenção & controle , Medição de Risco , Armas Biológicas , Pesquisa Biomédica , Bioterrorismo/prevenção & controle , Humanos , Saúde PúblicaRESUMO
In support of the response to the 2013-2016 Ebola virus disease (EVD) outbreak in Western Africa, we investigated the persistence of Ebola virus/H.sapiens-tc/GIN/2014/Makona-C05 (EBOV/Mak-C05) on non-porous surfaces that are representative of hospitals, airplanes, and personal protective equipment. We performed persistence studies in three clinically-relevant human fluid matrices (blood, simulated vomit, and feces), and at environments representative of in-flight airline passenger cabins, environmentally-controlled hospital rooms, and open-air Ebola treatment centers in Western Africa. We also compared the surface stability of EBOV/Mak-C05 to that of the prototype Ebola virus/H.sapiens-tc/COD/1976/Yambuku-Mayinga (EBOV/Yam-May), in a subset of these conditions. We show that on inert, non-porous surfaces, EBOV decay rates are matrix- and environment-dependent. Among the clinically-relevant matrices tested, EBOV persisted longest in dried human blood, had limited viability in dried simulated vomit, and did not persist in feces. EBOV/Mak-C05 and EBOV/Yam-May decay rates in dried matrices were not significantly different. However, during the drying process in human blood, EBOV/Yam-May showed significantly greater loss in viability than EBOV/Mak-C05 under environmental conditions relevant to the outbreak region, and to a lesser extent in conditions relevant to an environmentally-controlled hospital room. This factor may contribute to increased communicability of EBOV/Mak-C05 when surfaces contaminated with dried human blood are the vector and may partially explain the magnitude of the most recent outbreak, compared to prior outbreaks. These EBOV persistence data will improve public health efforts by informing risk assessments, structure remediation decisions, and response procedures for future EVD outbreaks.
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Ebolavirus/fisiologia , Equipamento de Proteção Individual/virologia , Animais , Sangue/virologia , Chlorocebus aethiops , Ebolavirus/patogenicidade , Fezes/virologia , Humanos , Umidade , Especificidade da Espécie , Células Vero/virologia , Vômito/virologiaRESUMO
The endosomal sorting complexes required for transport (ESCRT) proteins mediate fundamental membrane remodeling events that require stabilizing negative membrane curvature. These include endosomal intralumenal vesicle formation, HIV budding, nuclear envelope closure, and cytokinetic abscission. ESCRT-III subunits perform key roles in these processes by changing conformation and polymerizing into membrane-remodeling filaments. Here, we report the 4 angstrom resolution cryogenic electron microscopy reconstruction of a one-start, double-stranded helical copolymer composed of two different human ESCRT-III subunits, charged multivesicular body protein 1B (CHMP1B) and increased sodium tolerance 1 (IST1). The inner strand comprises "open" CHMP1B subunits that interlock in an elaborate domain-swapped architecture and is encircled by an outer strand of "closed" IST1 subunits. Unlike other ESCRT-III proteins, CHMP1B and IST1 polymers form external coats on positively curved membranes in vitro and in vivo. Our analysis suggests how common ESCRT-III filament architectures could stabilize different degrees and directions of membrane curvature.
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Complexos Endossomais de Distribuição Requeridos para Transporte/química , Proteínas Oncogênicas/química , Biopolímeros/química , Membrana Celular/química , Membrana Celular/ultraestrutura , Microscopia Crioeletrônica , Humanos , Estrutura Secundária de Proteína , Estrutura Terciária de ProteínaRESUMO
The endosomal sorting complexes required for transport (ESCRT) pathway was initially defined in yeast genetic screens that identified the factors necessary to sort membrane proteins into intraluminal endosomal vesicles. Subsequent studies have revealed that the mammalian ESCRT pathway also functions in a series of other key cellular processes, including formation of extracellular microvesicles, enveloped virus budding, and the abscission stage of cytokinesis. The core ESCRT machinery comprises Bro1 family proteins and ESCRT-I, ESCRT-II, ESCRT-III, and VPS4 complexes. Site-specific adaptors recruit these soluble factors to assemble on different cellular membranes, where they carry out membrane fission reactions. ESCRT-III proteins form filaments that draw membranes together from the cytoplasmic face, and mechanistic models have been advanced to explain how ESCRT-III filaments and the VPS4 ATPase can work together to catalyze membrane fission.
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Membrana Celular/metabolismo , Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo , Proteínas de Membrana/metabolismo , Transdução de Sinais/fisiologia , Animais , Complexos Endossomais de Distribuição Requeridos para Transporte/química , Humanos , Mamíferos , Transporte ProteicoRESUMO
The ESCRT pathway helps mediate the final abscission step of cytokinesis in mammals and archaea. In mammals, two early acting proteins of the ESCRT pathway, ALIX and TSG101, are recruited to the midbody through direct interactions with the phosphoprotein CEP55. CEP55 resides at the centrosome through most of the cell cycle but then migrates to the midbody at the start of cytokinesis, suggesting that the ESCRT pathway may also have centrosomal links. Here, we have systematically analyzed the requirements for late-acting mammalian ESCRT-III and VPS4 proteins at different stages of mitosis and cell division. We found that depletion of VPS4A, VPS4B, or any of the 11 different human ESCRT-III (CHMP) proteins inhibited abscission. Remarkably, depletion of individual ESCRT-III and VPS4 proteins also altered centrosome and spindle pole numbers, producing multipolar spindles (most ESCRT-III/VPS4 proteins) or monopolar spindles (CHMP2A or CHMP5) and causing defects in chromosome segregation and nuclear morphology. VPS4 proteins concentrated at spindle poles during mitosis and then at midbodies during cytokinesis, implying that these proteins function directly at both sites. We conclude that ESCRT-III/VPS4 proteins function at centrosomes to help regulate their maintenance or proliferation and then at midbodies during abscission, thereby helping ensure the ordered progression through the different stages of cell division.
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Adenosina Trifosfatases/metabolismo , Centrossomo/metabolismo , Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo , Fuso Acromático/metabolismo , ATPases Associadas a Diversas Atividades Celulares , Adenosina Trifosfatases/deficiência , Biomarcadores Tumorais/metabolismo , Sobrevivência Celular , Citocinese , DNA/metabolismo , Complexos Endossomais de Distribuição Requeridos para Transporte/deficiência , Células HeLa , Humanos , Imageamento Tridimensional , Mitose , Transporte Proteico , Fatores de Tempo , ATPases Vacuolares Próton-TranslocadorasRESUMO
Mouse T cell clone 2C recognizes two different major histocompatibility (MHC) ligands, the self MHC K(b) and the allogeneic MHC L(d). Two distinct peptides, SIY (SIYRYYGL) and QL9 (QLSPFPFDL), act as strong and specific agonists when bound to K(b) and L(d), respectively. To explore further the mechanisms involved in peptide potency and specificity, here we examined a collection of single amino acid peptide variants of SIY and QL9 for 1) T cell activity, 2) binding to their respective MHC, and 3) binding to the 2C T cell receptor (TCR) and high affinity TCR mutants. Characterization of SIY binding to MHC K(b) revealed significant effects of three SIY residues that were clearly embedded within the K(b) molecule. In contrast, QL9 binding to MHC L(d) was influenced by the majority of peptide side chains, distributed across the entire length of the peptide. Binding of the SIY-K(b) complex to the TCR involved three SIY residues that were pointed toward the TCR, whereas again the majority of QL9 residues influenced binding of TCRs, and thus the QL9 residues had impacts on both L(d) and TCR binding. In general, the magnitude of T cell activity mediated by a peptide variant was influenced more by peptide binding to MHC than by binding the TCR, especially for higher affinity TCRs. Findings with both systems, but QL9-L(d) in particular, suggest that many single-residue substitutions, introduced into peptides to improve their binding to MHC and thus their vaccine potential, could impair T cell reactivity due to their dual impact on TCR binding.
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Complexo Principal de Histocompatibilidade , Peptídeos/química , Receptores de Antígenos de Linfócitos T/química , Animais , Sítios de Ligação , Membrana Celular/metabolismo , Relação Dose-Resposta a Droga , Ativação Linfocitária , Camundongos , Conformação Molecular , Oligopeptídeos/química , Ligação Proteica , Estrutura Terciária de Proteína , Linfócitos T/citologiaRESUMO
To understand the mechanisms that govern T cell receptor (TCR)-peptide MHC (pMHC) binding and the role that different regions of the TCR play in affinity and antigen specificity, we have studied the TCR from T cell clone 2C. High-affinity mutants of the 2C TCR that bind QL9-L(d) as a strong agonist were generated previously by site-directed mutagenesis of complementarity determining regions (CDRs) 1beta, 2alpha, 3alpha, or 3beta. We performed isothermal titration calorimetry to assess whether they use similar thermodynamic mechanisms to achieve high affinity for QL9-L(d). Four of the five TCRs examined bound to QL9-L(d) in an enthalpically driven, entropically unfavorable manner. In contrast, the high-affinity CDR1beta mutant resembled the wild-type 2C TCR interaction, with favorable entropy. To assess fine specificity, we measured the binding and kinetics of these mutants for both QL9-L(d) and a single amino acid peptide variant of QL9, called QL9-Y5-L(d). While 2C and most of the mutants had equal or higher affinity for the Y5 variant than for QL9, mutant CDR1beta exhibited 8-fold lower affinity for Y5 compared to QL9. To examine possible structural correlates of the thermodynamic and fine specificity signatures of the TCRs, the structure of unliganded QL9-L(d) was solved and compared to structures of the 2C TCR/QL9-L(d) complex and three high-affinity TCR/QL9-L(d) complexes. Our findings show that the QL9-L(d) complex does not undergo major conformational changes upon binding. Thus, subtle changes in individual CDRs account for the diverse thermodynamic and kinetic binding mechanisms and for the different peptide fine specificities.
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Oligopeptídeos/metabolismo , Receptores de Antígenos de Linfócitos T/química , Receptores de Antígenos de Linfócitos T/metabolismo , Sequência de Aminoácidos , Animais , Cricetinae , Cinética , Ligantes , Camundongos , Modelos Moleculares , Mutação , Oligopeptídeos/química , Ligação Proteica , Conformação Proteica , Ratos , Receptores de Antígenos de Linfócitos T/genética , Especificidade por Substrato , Termodinâmica , TransfecçãoRESUMO
T cells are known to cross-react with diverse peptide MHC Ags through their alphabeta TCR. To explore the basis of such cross-reactivity, we examined the 2C TCR that recognizes two structurally distinct ligands, SIY-K(b) and alloantigen QL9-L(d). In this study we characterized the cross-reactivity of several high-affinity 2C TCR variants that contained mutations only in the CDR3alpha loop. Two of the TCR lost their ability to cross-react with the reciprocal ligand (SIY-K(b)), whereas another TCR (m67) maintained reactivity with both ligands. Crystal structures of four of the TCRs in complex with QL9-L(d) showed that CDR1, CDR2, and CDR3beta conformations and docking orientations were remarkably similar. Although the CDR3alpha loop of TCR m67 conferred a 2000-fold higher affinity for SIY-K(b), the TCR maintained the same docking angle on QL9-L(d) as the 2C TCR. Thus, CDR3alpha dictated the affinity and level of cross-reactivity, yet it did so without affecting the conserved docking orientation.
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Regiões Determinantes de Complementaridade/química , Antígenos H-2/metabolismo , Oligopeptídeos/metabolismo , Receptores de Antígenos de Linfócitos T alfa-beta/química , Sequência de Aminoácidos , Animais , Regiões Determinantes de Complementaridade/genética , Regiões Determinantes de Complementaridade/metabolismo , Sequência Conservada , Reações Cruzadas/genética , Reações Cruzadas/imunologia , Antígenos H-2/química , Antígenos H-2/genética , Antígeno de Histocompatibilidade H-2D , Complexo Cetoglutarato Desidrogenase/genética , Complexo Cetoglutarato Desidrogenase/imunologia , Complexo Cetoglutarato Desidrogenase/metabolismo , Camundongos , Dados de Sequência Molecular , Oligopeptídeos/química , Oligopeptídeos/genética , Oligopeptídeos/imunologia , Ligação Proteica/genética , Ligação Proteica/imunologia , Transporte Proteico/genética , Transporte Proteico/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismoRESUMO
Interleukin-4 and Interleukin-13 are cytokines critical to the development of T cell-mediated humoral immune responses, which are associated with allergy and asthma, and exert their actions through three different combinations of shared receptors. Here we present the crystal structures of the complete set of type I (IL-4R alpha/gamma(c)/IL-4) and type II (IL-4R alpha/IL-13R alpha1/IL-4, IL-4R alpha/IL-13R alpha1/IL-13) ternary signaling complexes. The type I complex reveals a structural basis for gamma(c)'s ability to recognize six different gamma(c)-cytokines. The two type II complexes utilize an unusual top-mounted Ig-like domain on IL-13R alpha1 for a novel mode of cytokine engagement that contributes to a reversal in the IL-4 versus IL-13 ternary complex assembly sequences, which are mediated through substantially different recognition chemistries. We also show that the type II receptor heterodimer signals with different potencies in response to IL-4 versus IL-13 and suggest that the extracellular cytokine-receptor interactions are modulating intracellular membrane-proximal signaling events.
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Interleucina-13/metabolismo , Interleucina-4/metabolismo , Receptores de Citocinas/metabolismo , Receptores de Interleucina-13/metabolismo , Receptores de Interleucina-4/metabolismo , Sequência de Aminoácidos , Sítios de Ligação , Linhagem Celular , Linhagem Celular Tumoral , Cristalografia por Raios X , Dimerização , Relação Dose-Resposta a Droga , Histidina/metabolismo , Humanos , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Interleucina-13/genética , Interleucina-13/isolamento & purificação , Interleucina-13/farmacologia , Interleucina-4/genética , Interleucina-4/isolamento & purificação , Interleucina-4/farmacologia , Cinética , Ligantes , Modelos Moleculares , Mimetismo Molecular , Dados de Sequência Molecular , Fosforilação , Ligação Proteica , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Receptores de Citocinas/química , Receptores de Interleucina-13/química , Receptores de Interleucina-4/química , Proteínas Recombinantes/metabolismo , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT6/metabolismo , Homologia de Sequência de Aminoácidos , Transdução de Sinais , Termodinâmica , Tirosina/metabolismo , Difração de Raios XRESUMO
Measles virus is a highly pathogenic virus that infects roughly 20 million people per year. We report here the crystal structure of the measles virus hemagglutinin, the surface glycoprotein responsible for the binding of measles virus to its host cell receptors. Although the protein lacks neuraminidase activity, its structure resembles a 'dead' neuraminidase fold, presenting spatially distinct receptor-binding sites for its receptors CD46 and SLAM.
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Hemaglutininas Virais/química , Vírus do Sarampo/química , Sítios de Ligação , Hemaglutininas Virais/metabolismo , Modelos Moleculares , Conformação ProteicaRESUMO
T cell receptor (TCR) recognition of peptide-MHC (pMHC) is central to the cellular immune response. A large database of TCR-pMHC structures is needed to reveal general structural principles, such as whether the repertoire of TCR/MHC docking modes is dictated by a "recognition code" between conserved elements of the TCR and MHC genes. Although approximately 17 cocrystal structures of unique TCR-pMHC complexes have been determined, cocrystallization of soluble TCR and pMHC remains a major technical obstacle in the field. Here we demonstrate a strategy, based on NMR chemical shift mapping, that permits rapid and reliable analysis of the solution footprint made by a TCR when binding onto the pMHC surface. We mapped the 2C TCR binding interaction with its allogeneic ligand H-2Ld-QL9 and identified a group of NMR-shifted residues that delineated a clear surface of the MHC that we defined as the TCR footprint. We subsequently found that the docking footprint described by NMR shifts was highly accurate compared with a recently determined high-resolution crystal structure of the same complex. The same NMR footprint analysis was done on a high-affinity mutant of the TCR. The current work serves as a foundation to explore the molecular dynamics of pMHC complexes and to rapidly determine the footprints of many Ld-specific TCRs.
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Antígenos H-2/química , Receptores de Antígenos de Linfócitos T/química , Sequência de Aminoácidos , Animais , Regiões Determinantes de Complementaridade , Antígeno de Histocompatibilidade H-2D , Espectroscopia de Ressonância Magnética , Camundongos , Dados de Sequência Molecular , Dobramento de ProteínaRESUMO
alphabeta T cell receptors (TCRs) can crossreact with both self- and foreign- major histocompatibility complex (MHC) proteins in an enigmatic phenomenon termed alloreactivity. Here we present the 2.35 A structure of the 2C TCR complexed with its foreign ligand H-2L(d)-QL9. Surprisingly, we find that this TCR utilizes a different strategy to engage the foreign pMHC in comparison to the manner in which it recognizes a self ligand H-2K(b)-dEV8. 2C engages both shared and polymorphic residues on L(d) and K(b), as well as the unrelated QL9 and dEV8 peptide antigens, in unique pair-wise contacts, resulting in greater structural complementarity with the L(d)-QL9 complex. In the structure of an engineered, high-affinity 2C TCR variant bound to H-2L(d)-QL9, the "wild-type" TCR-MHC binding orientation persists despite modified TCR-CDR3alpha interactions with peptide. Thus, a single TCR recognizes two globally similar, but distinct ligands by divergent mechanisms, indicating that receptor-ligand crossreactivity can occur in the absence of molecular mimicry.
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Autoantígenos/imunologia , Antígenos H-2/imunologia , Isoantígenos/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Sequência de Aminoácidos , Autoantígenos/química , Autoantígenos/metabolismo , Regiões Determinantes de Complementaridade/metabolismo , Cristalografia por Raios X , Antígenos H-2/química , Antígenos H-2/metabolismo , Antígeno de Histocompatibilidade H-2D , Isoantígenos/química , Isoantígenos/metabolismo , Complexo Cetoglutarato Desidrogenase/química , Complexo Cetoglutarato Desidrogenase/imunologia , Ligantes , Modelos Moleculares , Dados de Sequência Molecular , Peptídeos/química , Peptídeos/imunologia , Peptídeos/metabolismo , Ligação Proteica , Receptores de Antígenos de Linfócitos T alfa-beta/química , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismoRESUMO
The major histocompatibility complex (MHC) is the most polymorphic locus known, with thousands of allelic variants. There is considerable interest in understanding the diversity of structures and peptide-binding features represented by this class of proteins. Although many MHC proteins have been crystallized, others have not been amenable to structural or biochemical studies due to problems with expression or stability. In the present study, yeast display was used to engineer stabilizing mutations into the class I MHC molecule, Ld. The approach was based on previous studies that showed surface levels of yeast-displayed fusion proteins are directly correlated with protein stability. To engineer a more stable Ld, we selected Ld mutants with increased surface expression from randomly mutated yeast display libraries using anti-Ld antibodies or high affinity, soluble T-cell receptors (TCRs). The most stable Ld mutant, Ld-m31, consisted of a single-chain MHC module containing only the alpha1 and alpha2 domains. The enhanced stability was in part due to a single mutation (Trp-97 --> Arg), shown previously to be present in the allele Lq. Mutant Ld-m31 could bind to Ld peptides, and the specific peptide.Ld-m31 complex (QL9.Ld-m31) was recognized by alloreactive TCR 2C. A soluble form of the Ld-m31 protein was expressed in Escherichia coli and refolded from inclusion bodies at high yields. Surface plasmon resonance showed that TCRs bound to peptide.Ld-m31 complexes with affinities similar to those of native full-length Ld. The TCR and QL9.Ld-m31 formed complexes that could be resolved by native gel electrophoresis, suggesting that stabilized alpha1/alpha2 class I platforms may enable various structural studies.
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Antígenos H-2/química , Complexo Principal de Histocompatibilidade , Alelos , Animais , Membrana Celular/metabolismo , Antígeno de Histocompatibilidade H-2D , Humanos , Camundongos , Mutação , Oligopeptídeos/química , Peptídeos/química , Ligação Proteica , Desnaturação Proteica , Dobramento de Proteína , Estrutura Terciária de Proteína , Proteínas Recombinantes de Fusão/química , Ressonância de Plasmônio de SuperfícieRESUMO
The E2 protein segregates episomal bovine papillomavirus (BPV) genomes to daughter cells by tethering them to mitotic chromosomes, thus ensuring equal distribution and retention of viral DNA. To date, only the BPV1 E2 protein has been shown to bind to mitotic chromosomes. We assessed the localization of 13 different animal and human E2 proteins from seven papillomavirus genera, and we show that most of them are stably bound to chromosomes throughout mitosis. Furthermore, in contrast to the random association of BPV1 E2 with mitotic chromosomes, several of these proteins appear to bind to more specific regions of mitotic chromosomes. Using human papillomavirus (HPV) type 8 E2, we show that this region is adjacent to centromeres/kinetochores. Therefore, E2 proteins from both HPV and animal papillomavirus bind to mitotic chromosomes, and there are variations in the specificity of this binding. Only the alpha-papillomavirus E2 proteins do not stably associate with mitotic chromatin throughout mitosis. These proteins closely associate with prophase chromosomes and bind to chromosomes in telophase but not in metaphase. However, extraction of mitotic cells before fixation results in alpha-E2 proteins binding to the pericentromeric region of metaphase chromosomes, as observed for HPV8 E2. We postulate that this is the authentic target of these E2 proteins but that additional factors or a specialized cellular environment is required to stabilize this association. Thus, E2-mediated tethering of viral genomes to mitotic chromosomes is a common strategy of papillomaviruses, but different viruses have evolved different variations of this theme.