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1.
Sci Immunol ; 2(11)2017 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-28763793

RESUMO

The intestinal mucosa is a key anatomical site for HIV-1 replication and CD4+ T cell depletion. Accordingly, in vivo treatment with an antibody to the gut-homing integrin α4ß7 was shown to reduce viral transmission, delay disease progression, and induce persistent virus control in macaques challenged with simian immunodeficiency virus (SIV). We show that integrin α4ß7 is efficiently incorporated into the envelope of HIV-1 virions. Incorporated α4ß7 is functionally active as it binds mucosal addressin cell adhesion molecule-1 (MAdCAM-1), promoting HIV-1 capture by and infection of MAdCAM-expressing cells, which in turn mediate trans-infection of bystander cells. Functional α4ß7 is present in circulating virions from HIV-infected patients and SIV-infected macaques, with peak levels during the early stages of infection. In vivo homing experiments documented selective and specific uptake of α4ß7+ HIV-1 virions by high endothelial venules in the intestinal mucosa. These results extend the paradigm of tissue homing to a retrovirus and are relevant for the pathogenesis, treatment, and prevention of HIV-1 infection.

2.
PLoS One ; 8(8): e74474, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24015319

RESUMO

Anthrax edema factor (EF) is a calmodulin-dependent adenylate cyclase that converts adenosine triphosphate (ATP) into 3'-5'-cyclic adenosine monophosphate (cAMP), contributing to the establishment of Bacillus anthracis infections and the resulting pathophysiology. We show that EF adenylate cyclase toxin activity is strongly mediated by the N-end rule, and thus is dependent on the identity of the N-terminal amino acid. EF variants having different N-terminal residues varied by more than 100-fold in potency in cultured cells and mice. EF variants having unfavorable, destabilizing N-terminal residues showed much greater activity in cells when the E1 ubiquitin ligase was inactivated or when proteasome inhibitors were present. Taken together, these results show that EF is uniquely affected by ubiquitination and/or proteasomal degradation.


Assuntos
Adenilil Ciclases/metabolismo , Antígenos de Bactérias/metabolismo , Bacillus anthracis/enzimologia , Toxinas Bacterianas/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteólise , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação , Adenilil Ciclases/genética , Animais , Antígenos de Bactérias/genética , Bacillus anthracis/genética , Toxinas Bacterianas/genética , Linhagem Celular , Camundongos
3.
J Mol Recognit ; 26(8): 376-81, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23784994

RESUMO

The monoclonal antibody S9.6 binds DNA-RNA hybrids with high affinity, making it useful in research and diagnostic applications, such as in microarrays and in the detection of R-loops. A single-chain variable fragment (scFv) of S9.6 was produced, and its affinities for various synthetic nucleic acid hybrids were measured by surface plasmon resonance (SPR). S9.6 exhibits dissociation constants of approximately 0.6 nM for DNA-RNA and, surprisingly, 2.7 nM for RNA-RNA hybrids that are AU-rich. The affinity of the S9.6 scFv did not appear to be strongly influenced by various buffer conditions or by ionic strength below 500 mM NaCl. The smallest epitope that was strongly bound by the S9.6 scFv contained six base pairs of DNA-RNA hybrid. Published 2013. This article is a U.S. Government work and is in the public domain in the USA.


Assuntos
Anticorpos Monoclonais/metabolismo , DNA/metabolismo , Ácidos Nucleicos Heteroduplexes/metabolismo , RNA/metabolismo , Anticorpos de Cadeia Única/metabolismo , Sequência de Aminoácidos , Anticorpos Monoclonais/isolamento & purificação , Afinidade de Anticorpos , Especificidade de Anticorpos , Soluções Tampão , Cátions Bivalentes/química , DNA/química , Epitopos/química , Epitopos/metabolismo , Concentração de Íons de Hidrogênio , Cinética , Dados de Sequência Molecular , Conformação de Ácido Nucleico , Ácidos Nucleicos Heteroduplexes/química , Concentração Osmolar , RNA/química , Anticorpos de Cadeia Única/isolamento & purificação , Ressonância de Plasmônio de Superfície
4.
J Biol Chem ; 288(13): 9058-65, 2013 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-23393143

RESUMO

Anthrax toxin protective antigen (PA) delivers its effector proteins into the host cell cytosol through formation of an oligomeric pore, which can assume heptameric or octameric states. By screening a highly directed library of PA mutants, we identified variants that complement each other to exclusively form octamers. These PA variants were individually nontoxic and demonstrated toxicity only when combined with their complementary partner. We then engineered requirements for activation by matrix metalloproteases and urokinase plasminogen activator into two of these variants. The resulting therapeutic toxin specifically targeted cells expressing both tumor associated proteases and completely stopped tumor growth in mice when used at a dose far below that which caused toxicity. This scheme for obtaining intercomplementing subunits can be employed with other oligomeric proteins and potentially has wide application.


Assuntos
Antígenos de Bactérias/química , Toxinas Bacterianas/química , Neoplasias/tratamento farmacológico , Animais , Bacillus anthracis/metabolismo , Linhagem Celular Tumoral , Feminino , Biblioteca Gênica , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Nus , Conformação Molecular , Mutação , Neoplasias/metabolismo , Plasmídeos/metabolismo , Conformação Proteica , Engenharia de Proteínas/métodos , Mapeamento de Interação de Proteínas/métodos , Estrutura Terciária de Proteína , Proteínas/química , Ultracentrifugação
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