Detalhes precisos de como um regulador mestre da expressão gênica se liga ao seu parceiro ativador podem abrir novos caminhos para o desenvolvimento de medicamentos contra o câncer.
![](data:image/jpeg;base64,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)
Os pesquisadores da AUST estão revelando novos detalhes sobre a proteína UHRF1, que é um dos alvos mais potentes para a terapêutica do câncer. Crédito: KAUST; Anastasia Serin
Detalhes precisos de como um regulador mestre da expressão gênica se liga ao seu parceiro ativador podem abrir novos caminhos para o desenvolvimento de medicamentos contra o câncer.
As descobertas revelam como o parceiro ativador, um pequeno metabólito celular e molécula sinalizadora chamada PI5P, interage simultaneamente com duas regiões diferentes da proteína reguladora UHRF1. Isso mostra como, quando se trata da modulação de proteínas complexas, os arranjos de ligação podem assumir formas elaboradas de várias partes.
A interação entre PI5P e UHRF1 exemplifica assim o velho ditado "O todo é maior que a soma das partes". Como Wolfgang Fischle, bioquímico da KAUST e autor do estudo, aponta, "regiões que ligam domínios separados de uma proteína de vários domínios podem ter uma funcionalidade importante na organização e, assim, regular a estrutura geral e a função de uma proteína".
Além disso, os insights biológicos básicos fornecidos pelo laboratório de Fischle na KAUST podem dar uma nova vida à busca por medicamentos direcionados ao UHRF1.
"Esta proteína é um dos alvos mais potentes para a terapêutica do câncer", diz Papita Mandal, pós-doutorando do grupo de Fischle. "Nossas descobertas ajudarão no planejamento estratégico no desenvolvimento de medicamentos contra ela".
Nossos genomas são marcados por marcadores químicos que ditam quais genes devem ser ativados ou silenciados a qualquer momento – um processo epigenético que, quando mal administrado, pode impulsionar o crescimento do tumor. UHRF1 desempenha um papel crítico na manutenção do arranjo adequado desses marcadores químicos durante a divisão celular , mas sua atividade depende da ligação ao PI5P.
Fischle e seus colegas em 2014 revelaram pela primeira vez que UHRF1 e PI5P eram parceiros vinculantes. No entanto, na época, "não estava claro como o regulamento realmente funcionava em nível molecular ", diz Fischle.
Desvendar os detalhes moleculares não era pouca coisa. O PI5P, um tipo de substância gordurosa conhecida como fosfolipídio, provou ser extremamente difícil de trabalhar. Os pesquisadores tiveram que implantar várias técnicas experimentais diferentes – bioquímicas, biofísicas, estruturais – para delinear a interação entre UHRF1 e seu parceiro de sinalização.
Em colaboração com o biólogo estrutural da KAUST, ?ukasz Jaremko, a proteômica Dalila Bensaddek e outros, eles descobriram que os alvos da ligação de PI5P eram duas regiões de ligação distantes de UHRF1 que conectavam diferentes domínios da proteína. E quando duplamente ligado desta forma, UHRF1 sofreu uma mudança conformacional que resultou em ativação funcional.
"Há muitas questões importantes a serem abordadas a seguir", observa Mandal. "A primeira é descobrir o significado fisiológico desta regulação." Armados com esse conhecimento, os pesquisadores esperam descobrir drogas que possam ter como alvo esse mecanismo de controle epigenético.