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-Structure paper
タイトル | The molecular basis of tRNA selectivity by human pseudouridine synthase 3. |
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ジャーナル・号・ページ | Mol Cell, Vol. 84, Issue 13, Page 2472-22489.e8, Year 2024 |
掲載日 | 2024年7月11日 |
![]() | Ting-Yu Lin / Leon Kleemann / Jakub Jeżowski / Dominika Dobosz / Michał Rawski / Paulina Indyka / Grzegorz Ważny / Rahul Mehta / Andrzej Chramiec-Głąbik / Łukasz Koziej / Tristan Ranff / Christian Fufezan / Mateusz Wawro / Jakub Kochan / Joanna Bereta / Sebastian A Leidel / Sebastian Glatt / ![]() ![]() ![]() |
PubMed 要旨 | Pseudouridine (Ψ), the isomer of uridine, is ubiquitously found in RNA, including tRNA, rRNA, and mRNA. Human pseudouridine synthase 3 (PUS3) catalyzes pseudouridylation of position 38/39 in tRNAs. ...Pseudouridine (Ψ), the isomer of uridine, is ubiquitously found in RNA, including tRNA, rRNA, and mRNA. Human pseudouridine synthase 3 (PUS3) catalyzes pseudouridylation of position 38/39 in tRNAs. However, the molecular mechanisms by which it recognizes its RNA targets and achieves site specificity remain elusive. Here, we determine single-particle cryo-EM structures of PUS3 in its apo form and bound to three tRNAs, showing how the symmetric PUS3 homodimer recognizes tRNAs and positions the target uridine next to its active site. Structure-guided and patient-derived mutations validate our structural findings in complementary biochemical assays. Furthermore, we deleted PUS1 and PUS3 in HEK293 cells and mapped transcriptome-wide Ψ sites by Pseudo-seq. Although PUS1-dependent sites were detectable in tRNA and mRNA, we found no evidence that human PUS3 modifies mRNAs. Our work provides the molecular basis for PUS3-mediated tRNA modification in humans and explains how its tRNA modification activity is linked to intellectual disabilities. |
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手法 | EM (単粒子) |
解像度 | 2.66 - 6.5 Å |
構造データ | EMDB-16917: Human apo pseudouridine synthase 3 (PUS3) EMDB-16926, PDB-8okd: EMDB-19830, PDB-9enb: EMDB-19831, PDB-9enc: EMDB-19832, PDB-9ene: EMDB-19833, PDB-9enf: ![]() EMDB-19834: Human pseudouridine synthase 3 (PUS3 R116A mutant) ![]() EMDB-19835: Human pseudouridine synthase 3 (PUS3 K119A mutant) ![]() EMDB-19836: Human pseudouridine synthase 3 (wild type) |
化合物 | ![]() ChemComp-MG: |
由来 |
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![]() | RNA BINDING PROTEIN / RNA modification / pseudouridylation / tRNA / homodimer |