The RRM-mediated RNA binding activity in T. brucei RAP1 is essential for VSG monoallelic expression.
The RRM-mediated RNA binding activity in T. brucei RAP1 is essential for VSG monoallelic expression.
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DOI：
10.1038/s41467-023-37307-0
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发表时间：
2023-03-22
影响因子：
16.6
通讯作者：
Li, Bibo
中科院分区：
文献类型：
--
作者：
Gaurav, Amit Kumar;Afrin, Marjia;Yang, Xian;Saha, Arpita;Sayeed, S. K. Abdus;Pan, Xuehua;Ji, Zeyang;Wong, Kam-Bo;Zhang, Mingjie;Zhao, Yanxiang;Li, Bibo
布鲁氏锥虫是一种引起非洲人类锥虫病的原生动物寄生虫。其主要表面抗原VSG从亚端粒位点以严格的单等位方式表达。我们之前发现，端粒蛋白TbRAP1通过其737RKRRR741补丁与dsDNA结合，从而在全球范围内沉默VSGs。TbRAP1如何允许单个活性VSG表达尚不清楚。通过核磁共振结构分析，我们意外地在TbRAP1中发现了一个RNA识别基序（RRM），这在RAP1同源物中是前所未有的。在737RKRRR741贴片的辅助下，TbRAP1 RRM在体外识别VSG 3’utrs的一致序列，并在体内结合活性VSG RNA。突变保守的RRM残基可消除RNA结合活性，显著降低活性VSG RNA水平，抑制沉默的VSG。TbRAP1的RNA与dsDNA结合活性之间的竞争提示了VSG单等位基因表达机制，在该机制中，活跃的VSG丰富的RNA拮抗TbRAP1的沉默作用，从而维持其全水平表达。单等位基因VSG的表达对布鲁氏锥虫的生存至关重要。TbRAP1的RNA和dsDNA结合活性之间的竞争确保了TbRAP1在维持活性VSG的高水平表达的同时，在全球范围内沉默其他VSG。
Trypanosoma brucei is a protozoan parasite that causes human African trypanosomiasis. Its major surface antigen VSG is expressed from subtelomeric loci in a strictly monoallelic manner. We previously showed that the telomere protein TbRAP1 binds dsDNA through its 737RKRRR741 patch to silence VSGs globally. How TbRAP1 permits expression of the single active VSG is unknown. Through NMR structural analysis, we unexpectedly identify an RNA Recognition Motif (RRM) in TbRAP1, which is unprecedented for RAP1 homologs. Assisted by the 737RKRRR741 patch, TbRAP1 RRM recognizes consensus sequences of VSG 3’UTRs in vitro and binds the active VSG RNA in vivo. Mutating conserved RRM residues abolishes the RNA binding activity, significantly decreases the active VSG RNA level, and derepresses silent VSGs. The competition between TbRAP1’s RNA and dsDNA binding activities suggests a VSG monoallelic expression mechanism in which the active VSG’s abundant RNA antagonizes TbRAP1’s silencing effect, thereby sustaining its full-level expression. Monoallelic VSG expression is essential for Trypanosoma brucei survival. Competition between TbRAP1’s RNA and dsDNA binding activities ensures that TbRAP1 sustains a high level expression of the active VSG while silencing other VSGs globally.
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影响因子：
2.6
作者：
Cestari I;Stuart K
通讯作者：
Stuart K
影响因子：
64.8
作者：
Jumper J;Evans R;Pritzel A;Green T;Figurnov M;Ronneberger O;Tunyasuvunakool K;Bates R;Žídek A;Potapenko A;Bridgland A;Meyer C;Kohl SAA;Ballard AJ;Cowie A;Romera-Paredes B;Nikolov S;Jain R;Adler J;Back T;Petersen S;Reiman D;Clancy E;Zielinski M;Steinegger M;Pacholska M;Berghammer T;Bodenstein S;Silver D;Vinyals O;Senior AW;Kavukcuoglu K;Kohli P;Hassabis D
通讯作者：
Hassabis D
DOI：
10.1038/nrmicro2145
发表时间：
2009-07
期刊：
Nature reviews. Microbiology
影响因子：
--
作者：
通讯作者：
--
影响因子：
3.4
作者：
Guizetti J;Scherf A
通讯作者：
Scherf A
影响因子：
16.6
作者：
Faria, Joana;Glover, Lucy;Horn, David
通讯作者：
Horn, David