IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v13y2022i1d10.1038_s41467-022-33123-0.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-33123-0
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-022-33123-0?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    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. 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.
    5. 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.
    6. 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.
    7. 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.
    8. 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.
    9. 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.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Nicolae Sapoval & Amirali Aghazadeh & Michael G. Nute & Dinler A. Antunes & Advait Balaji & Richard Baraniuk & C. J. Barberan & Ruth Dannenfelser & Chen Dun & Mohammadamin Edrisi & R. A. Leo Elworth &, 2022. "Current progress and open challenges for applying deep learning across the biosciences," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    2. Jianping Li & Yan Li & Akiko Koide & Huihui Kuang & Victor J. Torres & Shohei Koide & Da-Neng Wang & Nathaniel J. Traaseth, 2024. "Proton-coupled transport mechanism of the efflux pump NorA," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    3. Fengfeng Niu & Lingxuan Li & Lei Wang & Jinman Xiao & Shun Xu & Yong Liu & Leishu Lin & Cong Yu & Zhiyi Wei, 2024. "Autoinhibition and activation of myosin VI revealed by its cryo-EM structure," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    4. 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.
    5. J. Josephine Botsch & Roswitha Junker & Michèle Sorgenfrei & Patricia P. Ogger & Luca Stier & Susanne Gronau & Peter J. Murray & Markus A. Seeger & Brenda A. Schulman & Bastian Bräuning, 2024. "Doa10/MARCH6 architecture interconnects E3 ligase activity with lipid-binding transmembrane channel to regulate SQLE," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    6. Pablo Gallego & Maria-Jose Garcia-Bonete & Sergio Trillo-Muyo & Christian V. Recktenwald & Malin E. V. Johansson & Gunnar C. Hansson, 2023. "The intestinal MUC2 mucin C-terminus is stabilized by an extra disulfide bond in comparison to von Willebrand factor and other gel-forming mucins," Nature Communications, Nature, vol. 14(1), pages 1-9, December.
    7. Ye Yuan & Lei Chen & Kexu Song & Miaomiao Cheng & Ling Fang & Lingfei Kong & Lanlan Yu & Ruonan Wang & Zhendong Fu & Minmin Sun & Qian Wang & Chengjun Cui & Haojue Wang & Jiuyang He & Xiaonan Wang & Y, 2024. "Stable peptide-assembled nanozyme mimicking dual antifungal actions," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    8. Ivica Odorčić & Mohamed Belal Hamed & Sam Lismont & Lucía Chávez-Gutiérrez & Rouslan G. Efremov, 2024. "Apo and Aβ46-bound γ-secretase structures provide insights into amyloid-β processing by the APH-1B isoform," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    9. Stella Vitt & Simone Prinz & Martin Eisinger & Ulrich Ermler & Wolfgang Buckel, 2022. "Purification and structural characterization of the Na+-translocating ferredoxin: NAD+ reductase (Rnf) complex of Clostridium tetanomorphum," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    10. Pierre Azoulay & Joshua Krieger & Abhishek Nagaraj, 2024. "Old Moats for New Models: Openness, Control, and Competition in Generative AI," NBER Chapters, in: Entrepreneurship and Innovation Policy and the Economy, volume 4, National Bureau of Economic Research, Inc.
    11. Riya Shah & Thomas C. Panagiotou & Gregory B. Cole & Trevor F. Moraes & Brigitte D. Lavoie & Christopher A. McCulloch & Andrew Wilde, 2024. "The DIAPH3 linker specifies a β-actin network that maintains RhoA and Myosin-II at the cytokinetic furrow," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    12. Yashan Yang & Qianqian Shao & Mingcheng Guo & Lin Han & Xinyue Zhao & Aohan Wang & Xiangyun Li & Bo Wang & Ji-An Pan & Zhenguo Chen & Andrei Fokine & Lei Sun & Qianglin Fang, 2024. "Capsid structure of bacteriophage ΦKZ provides insights into assembly and stabilization of jumbo phages," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    13. Bret M. Boyd & Ian James & Kevin P. Johnson & Robert B. Weiss & Sarah E. Bush & Dale H. Clayton & Colin Dale, 2024. "Stochasticity, determinism, and contingency shape genome evolution of endosymbiotic bacteria," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    14. Jun-Yu Si & Yuan-Mei Chen & Ye-Hui Sun & Meng-Xue Gu & Mei-Ling Huang & Lu-Lu Shi & Xiao Yu & Xiao Yang & Qing Xiong & Cheng-Bao Ma & Peng Liu & Zheng-Li Shi & Huan Yan, 2024. "Sarbecovirus RBD indels and specific residues dictating multi-species ACE2 adaptiveness," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    15. Deyun Qiu & Jinxin V. Pei & James E. O. Rosling & Vandana Thathy & Dongdi Li & Yi Xue & John D. Tanner & Jocelyn Sietsma Penington & Yi Tong Vincent Aw & Jessica Yi Han Aw & Guoyue Xu & Abhai K. Tripa, 2022. "A G358S mutation in the Plasmodium falciparum Na+ pump PfATP4 confers clinically-relevant resistance to cipargamin," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    16. Shuo-Shuo Liu & Tian-Xia Jiang & Fan Bu & Ji-Lan Zhao & Guang-Fei Wang & Guo-Heng Yang & Jie-Yan Kong & Yun-Fan Qie & Pei Wen & Li-Bin Fan & Ning-Ning Li & Ning Gao & Xiao-Bo Qiu, 2024. "Molecular mechanisms underlying the BIRC6-mediated regulation of apoptosis and autophagy," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    17. Justin N. Vaughn & Sandra E. Branham & Brian Abernathy & Amanda M. Hulse-Kemp & Adam R. Rivers & Amnon Levi & William P. Wechter, 2022. "Graph-based pangenomics maximizes genotyping density and reveals structural impacts on fungal resistance in melon," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    18. Eliza S. Nieweglowska & Axel F. Brilot & Melissa Méndez-Moran & Claire Kokontis & Minkyung Baek & Junrui Li & Yifan Cheng & David Baker & Joseph Bondy-Denomy & David A. Agard, 2023. "The ϕPA3 phage nucleus is enclosed by a self-assembling 2D crystalline lattice," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    19. Sash Lopaticki & Robyn McConville & Alan John & Niall Geoghegan & Shihab Deen Mohamed & Lisa Verzier & Ryan W. J. Steel & Cindy Evelyn & Matthew T. O’Neill & Niccolay Madiedo Soler & Nichollas E. Scot, 2022. "Tryptophan C-mannosylation is critical for Plasmodium falciparum transmission," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    20. Radoslaw Pluta & Eric Aragón & Nicholas A. Prescott & Lidia Ruiz & Rebeca A. Mees & Blazej Baginski & Julia R. Flood & Pau Martin-Malpartida & Joan Massagué & Yael David & Maria J. Macias, 2022. "Molecular basis for DNA recognition by the maternal pioneer transcription factor FoxH1," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33123-0. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.