Characterization of Sequence-Specific Binding of LARP6 to the 5' Stem-Loop of Type I Collagen mRNAs and Implications for Rational Design of Antifibrotic Drugs.
Characterization of Sequence-Specific Binding of LARP6 to the 5' Stem-Loop of Type I Collagen mRNAs and Implications for Rational Design of Antifibrotic Drugs.
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DOI：
10.1016/j.jmb.2021.167394
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发表时间：
2022-01-30
影响因子：
5.6
通讯作者：
Stefanovic B
中科院分区：
文献类型：
--
作者：
Stefanovic L;Gordon BH;Silvers R;Stefanovic B
I型胶原蛋白的过度合成是纤维化疾病的标志。la相关蛋白6 （LARP6）与胶原mrna的5 '茎环（5sl）结合可调节其翻译，导致纤维化中胶原生物合成率的非自然升高。先前的研究表明，LARP6需要两个结构域与5sl RNA形成稳定的复合物，即La结构域和并列RNA识别基序（RRM），并称为La模块。在这里，我们描述了LARP6的La结构域以RNA序列特异性的方式识别5sl是必要的和充分的。位于连接第二个α-螺旋和La结构域β-片的柔性环中的一个三氨基酸基序，称为rnk基序，对结合至关重要。这三种氨基酸中的任何一种发生突变都会使La结构域与5sl的结合消失。LARP6与5sl RNA交联的主要位点也被定位到这个基序上。rnk基序在其他larp中没有发现，不能结合5sl。RRM的存在增加了La结构域与5sl RNA之间复合物的稳定性，RRM结构域与5sl RNA没有广泛的接触。我们提出了一个模型，其中LARP6对5sl的初始识别是由RNK表位介导的，并由RRM结构域进一步稳定。这一发现表明，LARP6与胶原mrna之间的相互作用可以被靶向RNK表位的小分子阻断，这将有助于合理设计LARP6结合抑制剂作为特异性抗纤维化药物。
Excessive synthesis of type I collagen is a hallmark of fibrotic diseases. Binding of La-related protein 6 (LARP6) to the 5’ stem-loop (5’SL) of collagen mRNAs regulates their translation leading to an unnaturally elevated rate of collagen biosynthesis in fibrosis. Previous work suggested that LARP6 needs two domains to form stable complex with 5’SL RNA, the La domain and the juxtaposed RNA recognition motif (RRM), jointly called the La-module. Here we describe that La domain of LARP6 is necessary and sufficient for recognition of 5’SL in RNA sequence specific manner. A three-amino-acid motif located in the flexible loop connecting the second α-helix to the β-sheet of the La domain, called the RNK-motif, is critical for binding. Mutation of any of these three amino acids abolishes the binding of the La domain to 5’SL. The major site of crosslinking of LARP6 to 5’SL RNA was mapped to this motif, as well. The RNK-motif is not found in other LARPs, which can not bind 5’SL. Presence of RRM increases the stability of complex between La domain and 5’SL RNA and RRM domain does not make extensive contacts with 5’SL RNA. We propose a model in which the initial recognition of 5’SL by LARP6 is mediated by the RNK epitope and further stabilized by the RRM domain. This discovery suggests that the interaction between LARP6 and collagen mRNAs can be blocked by small molecules that target the RNK epitope and will help rational design of the LARP6 binding inhibitors as specific antifibrotic drugs.
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影响因子：
14.9
作者：
Martino L;Pennell S;Kelly G;Busi B;Brown P;Atkinson RA;Salisbury NJ;Ooi ZH;See KW;Smerdon SJ;Alfano C;Bui TT;Conte MR
通讯作者：
Conte MR
影响因子：
14.9
作者：
Cavaluzzi, MJ;Borer, PN
通讯作者：
Borer, PN
DOI：
10.1080/15384101.2016.1152435
发表时间：
2016-07-02
期刊：
Cell cycle (Georgetown, Tex.)
影响因子：
--
作者：
Makarev E;Izumchenko E;Aihara F;Wysocki PT;Zhu Q;Buzdin A;Sidransky D;Zhavoronkov A;Atala A
通讯作者：
Atala A
影响因子：
1.6
作者：
Castro, Jose M.;Horn, Daniel A.;Lewis, Karen A.
通讯作者：
Lewis, Karen A.
影响因子：
7.7
作者：
Mattijssen S;Arimbasseri AG;Iben JR;Gaidamakov S;Lee J;Hafner M;Maraia RJ
通讯作者：
Maraia RJ