Structural basis of gRNA stabilization and mRNA recognition in trypanosomal RNA editing.

Science (New York, N.Y.) 2023 Jul 07

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In Trypanosoma brucei, the editosome, composed of RNA-editing substrate-binding complex (RESC) and RNA-editing catalytic complex (RECC), orchestrates guide RNA (gRNA)-programmed editing to recode cryptic mitochondrial transcripts into messenger RNAs (mRNAs). The mechanism of information transfer from gRNA to mRNA is unclear owing to a lack of high-resolution structures for these complexes. With cryo-electron microscopy and functional studies, we have captured gRNA-stabilizing RESC-A and gRNA-mRNA-binding RESC-B and RESC-C particles. RESC-A sequesters gRNA termini, thus promoting hairpin formation and blocking mRNA access. The conversion of RESC-A into RESC-B or -C unfolds gRNA and allows mRNA selection. The ensuing gRNA-mRNA duplex protrudes from RESC-B, likely exposing editing sites to RECC-catalyzed cleavage, uridine insertion or deletion, and ligation. Our work reveals a remodeling event facilitating gRNA-mRNA hybridization and assembly of a macromolecular substrate for the editosome's catalytic modality.

Citation

Shiheng Liu, Hong Wang, Xiaorun Li, Fan Zhang, Jane K J Lee, Zihang Li, Clinton Yu, Jason J Hu, Xiaojing Zhao, Takuma Suematsu, Ana L Alvarez-Cabrera, Qiushi Liu, Liye Zhang, Lan Huang, Inna Aphasizheva, Ruslan Aphasizhev, Z Hong Zhou. Structural basis of gRNA stabilization and mRNA recognition in trypanosomal RNA editing. Science (New York, N.Y.). 2023 Jul 07;381(6653):eadg4725