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DMDA-PatA mediates RNA sequence-selective translation repression by anchoring eIF4A and DDX3 to GNG motifs

Author

Listed:
  • Hironori Saito

    (Wako
    Kashiwa)

  • Yuma Handa

    (Shinagawa)

  • Mingming Chen

    (Wako
    Kashiwa)

  • Tilman Schneider-Poetsch

    (Wako)

  • Yuichi Shichino

    (Wako)

  • Mari Takahashi

    (Tsurumi-ku)

  • Daniel Romo

    (Baylor University)

  • Minoru Yoshida

    (Wako
    Bunkyo-ku)

  • Alois Fürstner

    (Max-Planck-Institut für Kohlenforschung)

  • Takuhiro Ito

    (Tsurumi-ku)

  • Kaori Fukuzawa

    (Shinagawa
    Osaka University)

  • Shintaro Iwasaki

    (Wako
    Kashiwa)

Abstract

Small-molecule compounds that elicit mRNA-selective translation repression have attracted interest due to their potential for expansion of druggable space. However, only a limited number of examples have been reported to date. Here, we show that desmethyl desamino pateamine A (DMDA-PatA) represses translation in an mRNA-selective manner by clamping eIF4A, a DEAD-box RNA-binding protein, onto GNG motifs. By systematically comparing multiple eIF4A inhibitors by ribosome profiling, we found that DMDA-PatA has unique mRNA selectivity for translation repression. Unbiased Bind-n-Seq reveals that DMDA-PatA-targeted eIF4A exhibits a preference for GNG motifs in an ATP-independent manner. This unusual RNA binding sterically hinders scanning by 40S ribosomes. A combination of classical molecular dynamics simulations and quantum chemical calculations, and the subsequent development of an inactive DMDA-PatA derivative reveals that the positive charge of the tertiary amine on the trienyl arm induces G selectivity. Moreover, we identified that DDX3, another DEAD-box protein, is an alternative DMDA-PatA target with the same effects on eIF4A. Our results provide an example of the sequence-selective anchoring of RNA-binding proteins and the mRNA-selective inhibition of protein synthesis by small-molecule compounds.

Suggested Citation

  • Hironori Saito & Yuma Handa & Mingming Chen & Tilman Schneider-Poetsch & Yuichi Shichino & Mari Takahashi & Daniel Romo & Minoru Yoshida & Alois Fürstner & Takuhiro Ito & Kaori Fukuzawa & Shintaro Iwa, 2024. "DMDA-PatA mediates RNA sequence-selective translation repression by anchoring eIF4A and DDX3 to GNG motifs," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51635-9
    DOI: 10.1038/s41467-024-51635-9
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    References listed on IDEAS

    as
    1. Sergio Di Marco & Anne Cammas & Xian Jin Lian & Erzsebet Nagy Kovacs & Jennifer F. Ma & Derek T. Hall & Rachid Mazroui & John Richardson & Jerry Pelletier & Imed Eddine Gallouzi, 2012. "The translation inhibitor pateamine A prevents cachexia-induced muscle wasting in mice," Nature Communications, Nature, vol. 3(1), pages 1-12, January.
    2. Shintaro Iwasaki & Stephen N. Floor & Nicholas T. Ingolia, 2016. "Rocaglates convert DEAD-box protein eIF4A into a sequence-selective translational repressor," Nature, Nature, vol. 534(7608), pages 558-561, June.
    3. Kazuhiro Kashiwagi & Yuichi Shichino & Tatsuya Osaki & Ayako Sakamoto & Madoka Nishimoto & Mari Takahashi & Mari Mito & Friedemann Weber & Yoshiho Ikeuchi & Shintaro Iwasaki & Takuhiro Ito, 2021. "eIF2B-capturing viral protein NSs suppresses the integrated stress response," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    4. Lise Boussemart & Hélène Malka-Mahieu & Isabelle Girault & Delphine Allard & Oskar Hemmingsson & Gorana Tomasic & Marina Thomas & Christine Basmadjian & Nigel Ribeiro & Frédéric Thuaud & Christina Mat, 2014. "eIF4F is a nexus of resistance to anti-BRAF and anti-MEK cancer therapies," Nature, Nature, vol. 513(7516), pages 105-109, September.
    5. Karina Chan & Francis Robert & Christian Oertlin & Dana Kapeller-Libermann & Daina Avizonis & Johana Gutierrez & Abram Handly-Santana & Mikhail Doubrovin & Julia Park & Christina Schoepfer & Brandon S, 2019. "eIF4A supports an oncogenic translation program in pancreatic ductal adenocarcinoma," Nature Communications, Nature, vol. 10(1), pages 1-16, December.
    6. Andrew L. Wolfe & Kamini Singh & Yi Zhong & Philipp Drewe & Vinagolu K. Rajasekhar & Viraj R. Sanghvi & Konstantinos J. Mavrakis & Man Jiang & Justine E. Roderick & Joni Van der Meulen & Jonathan H. S, 2014. "RNA G-quadruplexes cause eIF4A-dependent oncogene translation in cancer," Nature, Nature, vol. 513(7516), pages 65-70, September.
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