IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-54833-7.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-54833-7
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-024-54833-7?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. 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. 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.
    10. 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.
    11. 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.
    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. 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.
    2. 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.
    3. Paloma García Casas & Michela Rossini & Linnea Påvénius & Mezida Saeed & Nikita Arnst & Sonia Sonda & Tânia Fernandes & Irene D’Arsiè & Matteo Bruzzone & Valeria Berno & Andrea Raimondi & Maria Livia , 2024. "Simultaneous detection of membrane contact dynamics and associated Ca2+ signals by reversible chemogenetic reporters," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    4. Huiyu Cai & Zuobai Zhang & Mingkai Wang & Bozitao Zhong & Quanxiao Li & Yuxuan Zhong & Yanling Wu & Tianlei Ying & Jian Tang, 2024. "Pretrainable geometric graph neural network for antibody affinity maturation," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    5. Nathalie Béchon & Nitzan Tal & Avigail Stokar-Avihail & Alon Savidor & Meital Kupervaser & Sarah Melamed & Gil Amitai & Rotem Sorek, 2024. "Diversification of molecular pattern recognition in bacterial NLR-like proteins," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    6. Amika Singla & Daniel J. Boesch & Ho Yee Joyce Fung & Chigozie Ngoka & Avery S. Enriquez & Ran Song & Daniel A. Kramer & Yan Han & Esther Banarer & Andrew Lemoff & Puneet Juneja & Daniel D. Billadeau , 2024. "Structural basis for Retriever-SNX17 assembly and endosomal sorting," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    7. Helena E. Sverak & Luke N. Yaeger & Liam J. Worrall & Condurache M. Vacariu & Amy J. Glenwright & Marija Vuckovic & Zayni-Dean Al Azawi & Ryan P. Lamers & Victoria A. Marko & Clarissa Skorupski & Arvi, 2024. "Cryo-EM characterization of the anydromuropeptide permease AmpG central to bacterial fitness and β-lactam antibiotic resistance," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    8. Marius Klein & Klemens Wild & Irmgard Sinning, 2024. "Multi-protein assemblies orchestrate co-translational enzymatic processing on the human ribosome," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    9. 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.
    10. Kenneth Bødkter Schou & Samuel Mandacaru & Muhammad Tahir & Nikola Tom & Ann-Sofie Nilsson & Jens S. Andersen & Matteo Tiberti & Elena Papaleo & Jiri Bartek, 2024. "Exploring the structural landscape of DNA maintenance proteins," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    11. Qianqian Ming & Daniel Antfolk & David A. Price & Anna Manturova & Elliot Medina & Srishti Singh & Charlotte Mason & Timothy H. Tran & Keiran S. M. Smalley & Daisy W. Leung & Vincent C. Luca, 2024. "Structural basis for mouse LAG3 interactions with the MHC class II molecule I-Ab," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    12. Cornelia Sala & Martin Würtz & Enrico Salvatore Atorino & Annett Neuner & Patrick Partscht & Thomas Hoffmann & Sebastian Eustermann & Elmar Schiebel, 2024. "An interaction network of inner centriole proteins organised by POC1A-POC1B heterodimer crosslinks ensures centriolar integrity," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    13. Yinghui Chen & Yunxin Xu & Di Liu & Yaoguang Xing & Haipeng Gong, 2024. "An end-to-end framework for the prediction of protein structure and fitness from single sequence," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    14. 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.
    15. Kehan Wu & Yingce Xia & Pan Deng & Renhe Liu & Yuan Zhang & Han Guo & Yumeng Cui & Qizhi Pei & Lijun Wu & Shufang Xie & Si Chen & Xi Lu & Song Hu & Jinzhi Wu & Chi-Kin Chan & Shawn Chen & Liangliang Z, 2024. "TamGen: drug design with target-aware molecule generation through a chemical language model," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    16. 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.
    17. 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.
    18. 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.
    19. 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.
    20. 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.

    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:15:y:2024:i:1:d:10.1038_s41467-024-54833-7. 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.