Department of Biochemistry, Emory University School of Medicine, 1510 Clifton Road, Atlanta, GA 30322, USA.
The Eunice Kennedy Shriver National Institutes of Child Health and Human Development, NIH, Bethesda, MD 20892, USA.
Cell. 2018 Mar 22;173(1):221-233.e12. doi: 10.1016/j.cell.2018.02.058. Epub 2018 Mar 15.
Tandem zinc finger (ZF) proteins are the largest and most rapidly diverging family of DNA-binding transcription regulators in mammals. ZFP568 represses a transcript of placental-specific insulin like growth factor 2 (Igf2-P0) in mice. ZFP568 binds a 24-base pair sequence-specific element upstream of Igf2-P0 via the eleven-ZF array. Both DNA and protein conformations deviate from the conventional one finger-three bases recognition, with individual ZFs contacting 2, 3, or 4 bases and recognizing thymine on the opposite strand. These interactions arise from a shortened minor groove caused by an AT-rich stretch, suggesting adaptability of ZF arrays to sequence variations. Despite conservation in mammals, mutations at Igf2 and ZFP568 reduce their binding affinity in chimpanzee and humans. Our studies provide important insights into the evolutionary and structural dynamics of ZF-DNA interactions that play a key role in mammalian development and evolution.
串联锌指 (ZF) 蛋白是哺乳动物中最大和分化最快的 DNA 结合转录调控因子家族。ZFP568 在小鼠中抑制胎盘特异性胰岛素样生长因子 2 (Igf2-P0) 的转录本。ZFP568 通过十一 ZF 结构域结合 Igf2-P0 上游的 24 碱基对序列特异性元件。DNA 和蛋白质构象都偏离了传统的一个手指三个碱基识别，单个 ZF 接触 2、3 或 4 个碱基，并识别对面链上的胸腺嘧啶。这些相互作用源于富含 AT 的延伸导致的短小沟，表明 ZF 结构域对序列变异的适应性。尽管在哺乳动物中保守，但 Igf2 和 ZFP568 的突变会降低其在黑猩猩和人类中的结合亲和力。我们的研究为 ZF-DNA 相互作用的进化和结构动态提供了重要的见解，这些相互作用在哺乳动物的发育和进化中起着关键作用。
