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Mechanistic understanding of human SLFN11

Author

Listed:
  • Felix J. Metzner

    (Ludwig-Maximilians-Universität München)

  • Simon J. Wenzl

    (Ludwig-Maximilians-Universität München)

  • Michael Kugler

    (Ludwig-Maximilians-Universität München)

  • Stefan Krebs

    (Ludwig-Maximilians-Universität München)

  • Karl-Peter Hopfner

    (Ludwig-Maximilians-Universität München)

  • Katja Lammens

    (Ludwig-Maximilians-Universität München)

Abstract

Schlafen 11 (SLFN11) is an interferon-inducible antiviral restriction factor with tRNA endoribonuclease and DNA binding functions. It is recruited to stalled replication forks in response to replication stress and inhibits replication of certain viruses such as the human immunodeficiency virus 1 (HIV-1) by modulating the tRNA pool. SLFN11 has been identified as a predictive biomarker in cancer, as its expression correlates with a beneficial response to DNA damage inducing anticancer drugs. However, the mechanism and interdependence of these two functions are largely unknown. Here, we present cryo-electron microscopy (cryo-EM) structures of human SLFN11 in its dimeric apoenzyme state, bound to tRNA and in complex with single-strand DNA. Full-length SLFN11 neither hydrolyses nor binds ATP and the helicase domain appears in an autoinhibited state. Together with biochemical and structure guided mutagenesis studies, our data give detailed insights into the mechanism of endoribonuclease activity as well as suggestions on how SLFN11 may block stressed replication forks.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33123-0
    DOI: 10.1038/s41467-022-33123-0
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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. 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.
    5. 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.
    6. 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.
    7. 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.
    8. 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.
    9. 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.
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