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<p>Circularly permuted group II introns (CP introns) consist of rearranged structural domains separated by two tethered exons, generating branched introns and circular exons via back-splicing. Structural and mechanistic understanding of circular RNA (circRNA) generation by CP introns remains elusive. We resolve cryo-electron microscopy structures of a natural CP intron in different states during back-splicing at a resolution of 2.5–2.9 Å. Domain 6 (D6) undergoes a conformational change of 65° after branching, to facilitate 3′-exon recognition and circularization. Previously unseen tertiary interactions compact the catalytic triad and D6 for splicing without protein, whereas a metal ion, M<sub>35</sub>, is observed to stabilize the 5′-exon during splicing. While these unique features were not observed in canonical group II introns and spliceosomes, they are common in CP introns, as demonstrated by the cryo-EM structure of another CP intron discovered by comparative genomics analysis. Our results elucidate the mechanism of CP intron back-splicing dynamics, with potential applications in circRNA research and therapeutics.</p>

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Structural basis of circularly permuted group II intron self-splicing

  • 期刊论文

  • 发表日期：

    2025年1月31日

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  • Liu Wang,
  • Jiahao Xie,
  • Chong Zhang,
  • Jian Zou,
  • Zirui Huang,
  • Sitong Shang,
  • Xingyu Chen,
  • Yang Yang,
  • Jianquan Liu,
  • Haohao Dong,
  • Dingming Huang,
  • Zhaoming Su

摘要

Circularly permuted group II introns (CP introns) consist of rearranged structural domains separated by two tethered exons, generating branched introns and circular exons via back-splicing. Structural and mechanistic understanding of circular RNA (circRNA) generation by CP introns remains elusive. We resolve cryo-electron microscopy structures of a natural CP intron in different states during back-splicing at a resolution of 2.5–2.9 Å. Domain 6 (D6) undergoes a conformational change of 65° after branching, to facilitate 3′-exon recognition and circularization. Previously unseen tertiary interactions compact the catalytic triad and D6 for splicing without protein, whereas a metal ion, M35, is observed to stabilize the 5′-exon during splicing. While these unique features were not observed in canonical group II introns and spliceosomes, they are common in CP introns, as demonstrated by the cryo-EM structure of another CP intron discovered by comparative genomics analysis. Our results elucidate the mechanism of CP intron back-splicing dynamics, with potential applications in circRNA research and therapeutics.