The RRM-mediated RNA binding activity in T. brucei RAP1 is essential for VSG monoallelic expression

Amit Kumar Gaurav, Marjia Afrin, Xian Yang, Arpita Saha, S. K. Abdus Sayeed, Xuehua Pan, Zeyang Ji, Kam-Bo Wong, Mingjie Zhang, Yanxiang Zhao () and Bibo Li ()
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Amit Kumar Gaurav: Cleveland State University
Marjia Afrin: Cleveland State University
Xian Yang: The Hong Kong Polytechnic University, Hung Hom
Arpita Saha: Cleveland State University
S. K. Abdus Sayeed: Cleveland State University
Xuehua Pan: The Hong Kong Polytechnic University, Hung Hom
Zeyang Ji: Hong Kong University of Science and Technology, Clear Water Bay
Kam-Bo Wong: The Chinese University of Hong Kong (CUHK)
Mingjie Zhang: Hong Kong University of Science and Technology, Clear Water Bay
Yanxiang Zhao: The Hong Kong Polytechnic University, Hung Hom
Bibo Li: Cleveland State University

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-37307-0

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