Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 2 de 2
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Cell Death Differ ; 25(4): 721-734, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29459767

RESUMO

The prosurvival Bcl-2 family proteins Mcl-1 and Bcl-xL inhibit apoptosis by sequestering BH3-only proteins such as Bid and Bim (MODE 1) or the effector proteins Bak and Bax (MODE 2). To better understand the contributions of MODE 1 and MODE 2 in blocking cell death, and thus how to bypass resistance to cell death, we examined prescribed mixtures of Bcl-2 family proteins. In a Bim and Bak mixture, Bcl-xL and Mcl-1 each sequestered not only Bim but also Bak as it became activated by Bim. In contrast, in a Bid and Bak mixture, Bcl-xL preferentially sequestered Bid while Mcl-1 preferentially sequestered Bak. Notably, Bcl-xL could sequester Bak in response to the BH3 mimetic ABT-737, despite this molecule targeting Bcl-xL. These findings highlight the importance of Bak sequestration in resistance to anti-cancer treatments, including BH3 mimetics.


Assuntos
Compostos de Bifenilo/farmacologia , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Nitrofenóis/farmacologia , Sulfonamidas/farmacologia , Proteína Killer-Antagonista Homóloga a bcl-2/metabolismo , Proteína bcl-X/metabolismo , Animais , Camundongos , Camundongos Knockout , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Piperazinas/farmacologia , Proteína Killer-Antagonista Homóloga a bcl-2/genética , Proteína bcl-X/genética
2.
Nat Commun ; 6: 6841, 2015 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-25880232

RESUMO

During apoptosis, Bak permeabilizes mitochondria after undergoing major conformational changes, including poorly defined N-terminal changes. Here, we characterize those changes using 11 antibodies that were epitope mapped using peptide arrays and mutagenesis. After Bak activation by Bid, epitopes throughout the α1 helix are exposed indicating complete dissociation of α1 from α2 in the core and from α6-α8 in the latch. Moreover, disulfide tethering of α1 to α2 or α6 blocks cytochrome c release, suggesting that α1 dissociation is required for further conformational changes during apoptosis. Assaying epitope exposure when α1 is tethered shows that Bid triggers α2 movement, followed by α1 dissociation. However, α2 reaches its final position only after α1 dissociates from the latch. Thus, α1 dissociation is a key step in unfolding Bak into three major components, the N terminus, the core (α2-α5) and the latch (α6-α8).


Assuntos
Apoptose , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Proteína Killer-Antagonista Homóloga a bcl-2/metabolismo , Animais , Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/metabolismo , Linhagem Celular , Linhagem Celular Transformada , Mapeamento de Epitopos , Humanos , Camundongos , Mutagênese Sítio-Dirigida , Análise Serial de Proteínas
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...