Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 4 de 4
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Nat Commun ; 9(1): 1113, 2018 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-29535387

RESUMO

In the original version of this Article, extraneous text not belonging to the article was accidentally appended to end of the first paragraph of the discussion. This error has now been corrected in both the PDF and HTML versions of the Article.

2.
Nat Commun ; 8(1): 2281, 2017 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-29273753

RESUMO

Hundreds of non-proteinogenic (np) amino acids (AA) are found in plants and can in principle enter human protein synthesis through foods. While aminoacyl-tRNA synthetase (AARS) editing potentially provides a mechanism to reject np AAs, some have pathological associations. Co-crystal structures show that vegetable-sourced azetidine-2-carboxylic acid (Aze), a dual mimic of proline and alanine, is activated by both human prolyl- and alanyl-tRNA synthetases. However, it inserts into proteins as proline, with toxic consequences in vivo. Thus, dual mimicry increases odds for mistranslation through evasion of one but not both tRNA synthetase editing systems.


Assuntos
Alanina-tRNA Ligase/metabolismo , Aminoacil-tRNA Sintetases/metabolismo , Ácido Azetidinocarboxílico/metabolismo , Morte Celular , Mimetismo Molecular , RNA de Transferência/metabolismo , Alanina , Aminoácidos , Células HeLa , Humanos , Prolina , Biossíntese de Proteínas , Edição de RNA , Verduras
3.
Proc Natl Acad Sci U S A ; 113(50): 14300-14305, 2016 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-27911835

RESUMO

The 20 aminoacyl tRNA synthetases (aaRSs) couple each amino acid to their cognate tRNAs. During evolution, 19 aaRSs expanded by acquiring novel noncatalytic appended domains, which are absent from bacteria and many lower eukaryotes but confer extracellular and nuclear functions in higher organisms. AlaRS is the single exception, with an appended C-terminal domain (C-Ala) that is conserved from prokaryotes to humans but with a wide sequence divergence. In human cells, C-Ala is also a splice variant of AlaRS. Crystal structures of two forms of human C-Ala, and small-angle X-ray scattering of AlaRS, showed that the large sequence divergence of human C-Ala reshaped C-Ala in a way that changed the global architecture of AlaRS. This reshaping removes the role of C-Ala in prokaryotes for docking tRNA and instead repurposes it to form a dimer interface presenting a DNA-binding groove. This groove cannot form with the bacterial ortholog. Direct DNA binding by human C-Ala, but not by bacterial C-Ala, was demonstrated. Thus, instead of acquiring a novel appended domain like other human aaRSs, which engendered novel functions, a new AlaRS architecture was created by diversifying a preexisting appended domain.


Assuntos
Alanina-tRNA Ligase/química , Alanina-tRNA Ligase/genética , Alanina-tRNA Ligase/metabolismo , Processamento Alternativo , Sequência de Aminoácidos , Animais , Proteínas Arqueais/química , Proteínas Arqueais/genética , Proteínas Arqueais/metabolismo , Archaeoglobus fulgidus/enzimologia , Archaeoglobus fulgidus/genética , Sítios de Ligação , Sequência Conservada , Cristalografia por Raios X , DNA/metabolismo , Evolução Molecular , Humanos , Cinética , Modelos Moleculares , Domínios Proteicos , Multimerização Proteica , Estrutura Quaternária de Proteína , Homologia de Sequência de Aminoácidos , Eletricidade Estática
4.
Proc Natl Acad Sci U S A ; 113(30): 8460-5, 2016 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-27402763

RESUMO

Brain and heart pathologies are caused by editing defects of transfer RNA (tRNA) synthetases, which preserve genetic code fidelity by removing incorrect amino acids misattached to tRNAs. To extend understanding of the broader impact of synthetase editing reactions on organismal homeostasis, and based on effects in bacteria ostensibly from small amounts of mistranslation of components of the replication apparatus, we investigated the sensitivity to editing of the vertebrate genome. We show here that in zebrafish embryos, transient overexpression of editing-defective valyl-tRNA synthetase (ValRS(ED)) activated DNA break-responsive H2AX and p53-responsive downstream proteins, such as cyclin-dependent kinase (CDK) inhibitor p21, which promotes cell-cycle arrest at DNA damage checkpoints, and Gadd45 and p53R2, with pivotal roles in DNA repair. In contrast, the response of these proteins to expression of ValRS(ED) was abolished in p53-deficient fish. The p53-activated downstream signaling events correlated with suppression of abnormal morphological changes caused by the editing defect and, in adults, reversed a shortened life span (followed for 2 y). Conversely, with normal editing activities, p53-deficient fish have a normal life span and few morphological changes. Whole-fish deep sequencing showed genomic mutations associated with the editing defect. We suggest that the sensitivity of p53 to expression of an editing-defective tRNA synthetase has a critical role in promoting genome integrity and organismal homeostasis.


Assuntos
Aminoacil-tRNA Sintetases/metabolismo , Dano ao DNA , Proteína Supressora de Tumor p53/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Peixe-Zebra/metabolismo , Aminoacil-tRNA Sintetases/genética , Animais , Embrião não Mamífero/embriologia , Embrião não Mamífero/metabolismo , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Masculino , Mutação , Edição de RNA , Proteína Supressora de Tumor p53/genética , Peixe-Zebra/embriologia , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...