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Phosphorylation-mediated conformational change regulates human SLFN11

Author

Listed:
  • Michael Kugler

    (Ludwig-Maximilians-Universität München)

  • Felix J. Metzner

    (Ludwig-Maximilians-Universität München)

  • Gregor Witte

    (Ludwig-Maximilians-Universität München)

  • Karl-Peter Hopfner

    (Ludwig-Maximilians-Universität München)

  • Katja Lammens

    (Ludwig-Maximilians-Universität München)

Abstract

Human Schlafen 11 (SLFN11) is sensitizing cells to DNA damaging agents by irreversibly blocking stalled replication forks, making it a potential predictive biomarker in chemotherapy. Furthermore, SLFN11 acts as a pattern recognition receptor for single-stranded DNA (ssDNA) and functions as an antiviral restriction factor, targeting translation in a codon-usage-dependent manner through its endoribonuclease activity. However, the regulation of the various SLFN11 functions and enzymatic activities remains enigmatic. Here, we present cryo-electron microscopy (cryo-EM) structures of SLFN11 bound to tRNA-Leu and tRNA-Met that give insights into tRNA binding and cleavage, as well as its regulation by phosphorylation at S219 and T230. SLFN11 phosphomimetic mutant S753D adopts a monomeric conformation, shows ATP binding, but loses its ability to bind ssDNA and shows reduced ribonuclease activity. Thus, the phosphorylation site S753 serves as a conformational switch, regulating SLFN11 dimerization, as well as ATP and ssDNA binding, while S219 and T230 regulate tRNA recognition and nuclease activity.

Suggested Citation

  • Michael Kugler & Felix J. Metzner & Gregor Witte & Karl-Peter Hopfner & Katja Lammens, 2024. "Phosphorylation-mediated conformational change regulates human SLFN11," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-54833-7
    DOI: 10.1038/s41467-024-54833-7
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    as
    1. Kathryn Tunyasuvunakool & Jonas Adler & Zachary Wu & Tim Green & Michal Zielinski & Augustin Žídek & Alex Bridgland & Andrew Cowie & Clemens Meyer & Agata Laydon & Sameer Velankar & Gerard J. Kleywegt, 2021. "Highly accurate protein structure prediction for the human proteome," Nature, Nature, vol. 596(7873), pages 590-596, August.
    2. Jordi Barretina & Giordano Caponigro & Nicolas Stransky & Kavitha Venkatesan & Adam A. Margolin & Sungjoon Kim & Christopher J.Wilson & Joseph Lehár & Gregory V. Kryukov & Dmitriy Sonkin & Anupama Red, 2012. "Addendum: The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity," Nature, Nature, vol. 492(7428), pages 290-290, December.
    3. Jie Chen & Nan Liu & Yinpin Huang & Yuanxun Wang & Yuxing Sun & Qingcui Wu & Dianrong Li & Shuanhu Gao & Hong-Wei Wang & Niu Huang & Xiangbing Qi & Xiaodong Wang, 2021. "Structure of PDE3A–SLFN12 complex and structure-based design for a potent apoptosis inducer of tumor cells," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    4. Felix J. Metzner & Simon J. Wenzl & Michael Kugler & Stefan Krebs & Karl-Peter Hopfner & Katja Lammens, 2022. "Mechanistic understanding of human SLFN11," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    5. Manqing Li & Elaine Kao & Xia Gao & Hilary Sandig & Kirsten Limmer & Mariana Pavon-Eternod & Thomas E. Jones & Sebastien Landry & Tao Pan & Matthew D. Weitzman & Michael David, 2012. "Codon-usage-based inhibition of HIV protein synthesis by human schlafen 11," Nature, Nature, vol. 491(7422), pages 125-128, November.
    6. Jordi Barretina & Giordano Caponigro & Nicolas Stransky & Kavitha Venkatesan & Adam A. Margolin & Sungjoon Kim & Christopher J. Wilson & Joseph Lehár & Gregory V. Kryukov & Dmitriy Sonkin & Anupama Re, 2012. "The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity," Nature, Nature, vol. 483(7391), pages 603-607, March.
    7. Josh Abramson & Jonas Adler & Jack Dunger & Richard Evans & Tim Green & Alexander Pritzel & Olaf Ronneberger & Lindsay Willmore & Andrew J. Ballard & Joshua Bambrick & Sebastian W. Bodenstein & David , 2024. "Accurate structure prediction of biomolecular interactions with AlphaFold 3," Nature, Nature, vol. 630(8016), pages 493-500, June.
    8. Colin W. Garvie & Xiaoyun Wu & Malvina Papanastasiou & Sooncheol Lee & James Fuller & Gavin R. Schnitzler & Steven W. Horner & Andrew Baker & Terry Zhang & James P. Mullahoo & Lindsay Westlake & Steph, 2021. "Structure of PDE3A-SLFN12 complex reveals requirements for activation of SLFN12 RNase," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    9. Tristan Bepler & Kotaro Kelley & Alex J. Noble & Bonnie Berger, 2020. "Topaz-Denoise: general deep denoising models for cryoEM and cryoET," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
    10. Jin-Yu Yang & Xiang-Yu Deng & Yi-Sheng Li & Xian-Cai Ma & Jian-Xiong Feng & Bing Yu & Yang Chen & Yi-Ling Luo & Xi Wang & Mei-Ling Chen & Zhi-Xin Fang & Fu-Xiang Zheng & Yi-Ping Li & Qian Zhong & Tie-, 2018. "Structure of Schlafen13 reveals a new class of tRNA/rRNA- targeting RNase engaged in translational control," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
    11. John Jumper & Richard Evans & Alexander Pritzel & Tim Green & Michael Figurnov & Olaf Ronneberger & Kathryn Tunyasuvunakool & Russ Bates & Augustin Žídek & Anna Potapenko & Alex Bridgland & Clemens Me, 2021. "Highly accurate protein structure prediction with AlphaFold," Nature, Nature, vol. 596(7873), pages 583-589, August.
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    1. Justin Riper & Arleth O. Martinez-Claros & Lie Wang & Hannah E. Schneiderman & Sweta Maheshwari & Monica C. Pillon, 2025. "CryoEM structure of the SLFN14 endoribonuclease reveals insight into RNA binding and cleavage," Nature Communications, Nature, vol. 16(1), pages 1-15, December.

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