State Key Laboratory of Genetic Engineering, Collaborative Innovation Centre of Genetics and Development, Department of Biochemistry, Institute of Plant Biology, School of Life Sciences, Fudan University, Shanghai, 200438, China.
Department of Pharmacology, Weill Cornell Medicine, Cornell University, New York, NY, 10065, USA.
Nat Commun. 2018 Jan 29;9(1):420. doi: 10.1038/s41467-017-02770-z.
Human hnRNP A2/B1 is an RNA-binding protein that plays important roles in many biological processes, including maturation, transport, and metabolism of mRNA, and gene regulation of long noncoding RNAs. hnRNP A2/B1 was reported to control the microRNAs sorting to exosomes and promote primary microRNA processing as a potential mA "reader." hnRNP A2/B1 contains two RNA recognition motifs that provide sequence-specific recognition of RNA substrates. Here, we determine crystal structures of tandem RRM domains of hnRNP A2/B1 in complex with various RNA substrates, elucidating specific recognitions of AGG and UAG motifs by RRM1 and RRM2 domains, respectively. Further structural and biochemical results demonstrate multivariant binding modes for sequence-diversified RNA substrates, supporting a RNA matchmaker mechanism in hnRNP A2/B1 function. Moreover, our studies in combination with bioinformatic analysis suggest that hnRNP A2/B1 may mediate effects of mA through a "mA switch" mechanism, instead of acting as a direct "reader" of mA modification.
人类 hnRNP A2/B1 是一种 RNA 结合蛋白，在许多生物学过程中发挥着重要作用，包括 mRNA 的成熟、运输和代谢，以及长非编码 RNA 的基因调控。hnRNP A2/B1 被报道控制 microRNAs 向外泌体的分拣，并作为潜在的 mA“阅读器”促进初级 microRNA 加工。hnRNP A2/B1 包含两个 RNA 识别基序，为 RNA 底物提供序列特异性识别。在这里，我们确定了 hnRNP A2/B1 的串联 RRM 结构域与各种 RNA 底物复合物的晶体结构，分别阐明了 RRM1 和 RRM2 结构域对 AGG 和 UAG 基序的特异性识别。进一步的结构和生化结果表明，序列多样化的 RNA 底物具有多种结合模式，支持 hnRNP A2/B1 功能中的 RNA 匹配机制。此外，我们的研究结合生物信息学分析表明，hnRNP A2/B1 可能通过“mA 开关”机制介导 mA 的作用，而不是作为 mA 修饰的直接“阅读器”。
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