Acar Melih, Jafar-Nejad Hamed, Giagtzoglou Nikolaos, Yallampalli Sasidhar, David Gabriela, He Yuchun, Delidakis Christos, Bellen Hugo J
Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Development. 2006 May;133(10):1979-89. doi: 10.1242/dev.02372. Epub 2006 Apr 19.
The zinc-finger transcription factor Senseless is co-expressed with basic helix-loop-helix (bHLH) proneural proteins in Drosophila sensory organ precursors and is required for their normal development. High levels of Senseless synergize with bHLH proteins and upregulate target gene expression, whereas low levels of Senseless act as a repressor in vivo. However, the molecular mechanism for this dual role is unknown. Here, we show that Senseless binds bHLH proneural proteins via its core zinc fingers and is recruited by proneural proteins to their target enhancers to function as a co-activator. Some point mutations in the Senseless zinc-finger region abolish its DNA-binding ability but partially spare the ability of Senseless to synergize with proneural proteins and to induce sensory organ formation in vivo. Therefore, we propose that the structural basis for the switch between the repressor and co-activator functions of Senseless is the ability of its core zinc fingers to interact physically with both DNA and bHLH proneural proteins. As Senseless zinc fingers are approximately 90% identical to the corresponding zinc fingers of its vertebrate homologue Gfi1, which is thought to cooperate with bHLH proteins in several contexts, the Senseless/bHLH interaction might be evolutionarily conserved.
锌指转录因子无意义蛋白与果蝇感觉器官前体细胞中的碱性螺旋-环-螺旋（bHLH）原神经蛋白共同表达，且其正常发育需要该蛋白。高水平的无意义蛋白与bHLH蛋白协同作用并上调靶基因表达，而低水平的无意义蛋白在体内起阻遏作用。然而，这种双重作用的分子机制尚不清楚。在此，我们表明无意义蛋白通过其核心锌指与bHLH原神经蛋白结合，并被原神经蛋白招募至其靶增强子处发挥共激活因子的作用。无意义蛋白锌指区域的一些点突变消除了其DNA结合能力，但部分保留了无意义蛋白与原神经蛋白协同作用以及在体内诱导感觉器官形成的能力。因此，我们提出无意义蛋白阻遏功能与共激活功能之间转换的结构基础是其核心锌指与DNA和bHLH原神经蛋白发生物理相互作用的能力。由于无意义蛋白的锌指与其脊椎动物同源物Gfi1的相应锌指约90%相同，而Gfi1被认为在多种情况下与bHLH蛋白协同作用，因此无意义蛋白/bHLH相互作用可能在进化上是保守的。
