The research results of the Majin Biao team of Fudan University appeared on the main journal of "Nature"

RNA interference (RNAI) is a conservative RNA silent mechanism in many nuclear creatures. Small interference RNA is a key component of RNA interference. Among the fruit flies, the generation of SiRNA is a DICER-2 (DCR-2) protein, with its auxiliary factor LOQS-PD, cuts from the long dual-chain RNA (DSRNA) SiRNA. Dicer-2 is the earliest discovered ATP-dependent Dicer family protein. In 2000, it was found that the SIRNA processing process was dependent on ATP. In recent years, although there are many articles about the research on the biochemical and structural study of Dicer family protein, the molecular mechanism of the entire process of DICER protein recognition and cutting the RNA substrate of ATP is still unclear.

On June 29, 2022, the Team of Fudan University Majin Biao and the Wang Hongwei team of Tsinghua University published on the main journal of "Nature" magazine online entitled "Structural Insights INSIGHTS INTO DSRNA PROCESSING BY DROSOPHILA DICER-2 – Loqs-PD" Dicer-2 and LOQS-PD complexes in the structure of dual-chain RNA processing process ") article, which analyzes the separate protein including DICER-2-LOQS-PD, and DICER-2 – Loqs-PD. Without ATP, combined with the 6 sets of frozen electron microscope structures of DSRNA (Figure 1), combined with biochemical experiment analysis, the Dicer-2-Loqs-PD complex was first revealed The mechanism (Figure 2) solves key scientific issues that have troubled the small interference in the field of small interference for more than 20 years.

DICER-2 – LOQS-PD combined with the frozen electron microscope structure of dual-chain RNA complexes in different states

Earlier research reported that when the DICER-2 protein binding the substrate, there will be obvious structural changes. In addition, the DICER-2 protein dependent on ATP needs to move on the dual-chain RNA through hydrolyzed ATP during SIRNA processing, and continuously cuts continuously The process will inevitably lead to a complex in different states, and the three superimposed will have a great impact on the uniformity of the complex. In this regard, the research team began to analyze from the separate protein compound structure of the active site mutation; then added a dual-chain RNA, and when the ATP was obtained, the DICER-2 – Loqs-PD – DSRNA complex is in the initial binding state. Differential structures; on this basis, further join ATP, and through data collection and calculation classification, the state of cutting activity and two obvious displacement of different structural characteristics (early displacement and medium -term displacement state); then use normal use of normal The active DICER-2 protein obtained a complex after cutting, and found that it was shifting up early to change the state by analysis; thus stringing the entire process, clarifying the DICER-2 – Loqs-PD complex from combining from combining The dual -chain RNA moves on it to form a cut activity state until the cutting of the entire cycle of SIRNA and the continuous and progressive changes in the continuous and progressive conformity.

DICER-2 – LOQS-PD complex binding to the dual-chain RNA protein generating SIRNA processing cycle process mechanism model

Dr. Su Shichen from the School of Life Sciences of Fudan University and Dr. Wang Jia Wang from the School of Life Sciences of Tsinghua University as the first author of this article, Professor Ma Jinbiao of the School of Life Sciences of Fudan University, and Professor Wang Hongwei of the School of Life Sciences of Tsinghua University as the common communication author of this article. The research team of Huang Yan at Xinhua Hospital affiliated to Shanghai Jiaotong University School of Medicine also participated in the research work. National Protein Science Research (Beijing) Facilities Tsinghua Base and Mizuki Future (Beijing) Technology Co., Ltd. provide support for the collection and processing of frozen electron microscopes; the National Protein Science Center (Shanghai) provides support and help in mass spectrometer analysis. The research work has been supported by the National Natural Science Foundation of China, the National Key Laboratory of the National Key R & D Plan, the National Key Laboratory of the Genetics Engineering, the MRNA Innovation and Translation Center and the Scientific Exploration Award.

Link: https://www.nature.com/articleS/S41586-022-04911-X

Source: Academy of Life Sciences

Responsible editor: Zhang Peilin

Edit: Qin Yuan

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