Crystallography, Max-Delbrück Center for Molecular Medicine, Berlin 13125, Germany.
Int J Mol Sci. 2013 Aug 9;14(8):16532-53. doi: 10.3390/ijms140816532.
Lin28 is an essential RNA-binding protein that is ubiquitously expressed in embryonic stem cells. Its physiological function has been linked to the regulation of differentiation, development, and oncogenesis as well as glucose metabolism. Lin28 mediates these pleiotropic functions by inhibiting let-7 miRNA biogenesis and by modulating the translation of target mRNAs. Both activities strongly depend on Lin28's RNA-binding domains (RBDs), an N-terminal cold-shock domain (CSD) and a C-terminal Zn-knuckle domain (ZKD). Recent biochemical and structural studies revealed the mechanisms of how Lin28 controls let-7 biogenesis. Lin28 binds to the terminal loop of pri- and pre-let-7 miRNA and represses their processing by Drosha and Dicer. Several biochemical and structural studies showed that the specificity of this interaction is mainly mediated by the ZKD with a conserved GGAGA or GGAGA-like motif. Further RNA crosslinking and immunoprecipitation coupled to high-throughput sequencing (CLIP-seq) studies confirmed this binding motif and uncovered a large number of new mRNA binding sites. Here we review exciting recent progress in our understanding of how Lin28 binds structurally diverse RNAs and fulfills its pleiotropic functions.
Lin28 是一种必需的 RNA 结合蛋白，在胚胎干细胞中广泛表达。其生理功能与分化、发育和肿瘤发生以及葡萄糖代谢的调节有关。Lin28 通过抑制 let-7 miRNA 的生物发生并调节靶 mRNA 的翻译来介导这些多效性功能。这两种活性都强烈依赖于 Lin28 的 RNA 结合域（RBD），即 N 端冷休克域（CSD）和 C 端 Zn 指域（ZKD）。最近的生化和结构研究揭示了 Lin28 如何控制 let-7 生物发生的机制。Lin28 结合到 pri- 和 pre-let-7 miRNA 的末端环，并通过 Drosha 和 Dicer 抑制它们的加工。几项生化和结构研究表明，这种相互作用的特异性主要由 ZKD 介导，其具有保守的 GGAGA 或 GGAGA 样基序。进一步的 RNA 交联和免疫沉淀与高通量测序（CLIP-seq）研究证实了这种结合基序，并发现了大量新的 mRNA 结合位点。在这里，我们回顾了最近在理解 Lin28 如何结合结构多样的 RNA 并发挥其多效性功能方面取得的令人兴奋的进展。
