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用于解析LIN28对前体let-7微小RNA识别结构基础的分子动力学模拟

Molecular Dynamics Simulations for Deciphering the Structural Basis of Recognition of Pre-let-7 miRNAs by LIN28.

作者信息

Sharma Chhaya, Mohanty Debasisa

机构信息

Bioinformatics Center, National Institute of Immunology , Aruna Asaf Ali Marg, New Delhi 110067, India.

出版信息

Biochemistry. 2017 Feb 7;56(5):723-735. doi: 10.1021/acs.biochem.6b00837. Epub 2017 Jan 24.

Abstract

LIN28 protein inhibits biogenesis of miRNAs belonging to the let-7 family by binding to precursor forms of miRNAs. Overexpression of LIN28 and low levels of let-7 miRNAs are associated with several forms of cancer cells. We have performed multiple explicit solvent molecular dynamics simulations ranging from 200 to 500 ns in length on different isoforms of preE-let-7 in complex with LIN28 and also in isolation to identify structural features and key specificity-determining residues (SDRs) that are important for the inhibitory role of LIN28. Our simulations suggest that a conserved structural feature of the loop regions of preE-let-7 miRNAs is more important for LIN28 recognition than sequence conservation among members of the let-7 family or the presence of the GGAG motif in the 3' region. The loop region consisting of a minimum of five nucleotides helps pre-miRNAs to acquire a conformation ideal for binding to LIN28, but pre-let-7c-2 prefers a conformation with a three-nucleotide loop. Thus, our simulations provide a theoretical rationale for the recent experimental observation of the escape of LIN28-mediated repression by pre-let-7c-2. The essential structural and sequence features highlighted in this study might aid in designing synthetic small molecule inhibitors for modulating LIN28-let-7 interaction in malignant cells. We have also identified crucial SDRs of the LIN28-preE-let-7 complex involving 13 residues of LIN28 and 10 residues of the pre-miRNA. On the basis of the conservation profile of these 13 SDRs, we have identified 10 novel proteins that are not annotated as LIN28 like but are similar in sequence, domain, or fold level to LIN28.

摘要

LIN28蛋白通过与微小RNA(miRNA)的前体形式结合,抑制属于let-7家族的miRNA的生物合成。LIN28的过表达和低水平的let-7 miRNA与多种癌细胞相关。我们对与LIN28复合以及单独存在的preE-let-7的不同异构体进行了多个时长从200到500纳秒的显式溶剂分子动力学模拟,以确定对LIN28抑制作用重要的结构特征和关键的特异性决定残基(SDR)。我们的模拟表明,preE-let-7 miRNA环区的保守结构特征对LIN28识别比let-7家族成员间的序列保守性或3'区域中GGAG基序的存在更重要。由至少五个核苷酸组成的环区有助于前体miRNA获得与LIN28结合的理想构象,但pre-let-7c-2更喜欢具有三核苷酸环的构象。因此,我们的模拟为最近关于pre-let-7c-2逃避LIN28介导的抑制的实验观察提供了理论依据。本研究中突出的基本结构和序列特征可能有助于设计合成小分子抑制剂,以调节恶性细胞中LIN28与let-7的相互作用。我们还确定了LIN28-preE-let-7复合物的关键SDR,涉及LIN28的13个残基和前体miRNA的10个残基。基于这13个SDR的保守概况,我们鉴定了10种新蛋白,它们未被注释为类LIN28,但在序列、结构域或折叠水平上与LIN28相似。

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