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Structural basis for the human SENP5’s SUMO isoform discrimination

Author

Listed:
  • Lucía Sánchez-Alba

    (Universitat Autònoma de Barcelona)

  • Li Ying

    (Universitat Autònoma de Barcelona
    Qingdao University)

  • Matthew D. Maletic

    (Leiden University Medical Center (LUMC))

  • Anna Bolòs

    (Institut de Investigacions Biomèdiques Agustí Pi i Sunyer (IDIBABS))

  • Helena Borràs-Gas

    (Universitat Autònoma de Barcelona)

  • Bing Liu

    (Universitat Autònoma de Barcelona)

  • Nathalia Varejão

    (Universitat Autònoma de Barcelona)

  • Virginia Amador

    (Institut de Investigacions Biomèdiques Agustí Pi i Sunyer (IDIBABS))

  • Monique P. C. Mulder

    (Leiden University Medical Center (LUMC))

  • David Reverter

    (Universitat Autònoma de Barcelona)

Abstract

Post-translational SUMO modification is a widespread mechanism for regulating protein function within cells. In humans, SUMO-conjugated proteins are partially regulated by the deconjugating activity of six SENP family members. The proteolytic activity of these enzymes resides within a conserved catalytic domain that exhibits specificity for the two primary SUMO isoforms: SUMO1 and SUMO2/3. SENP5, along with SENP3, are nucleolar proteins involved in ribosome biogenesis and preferentially target SUMO2/3 isoforms. Here, we present the crystal structures of human SENP5 in complex with both SUMO1 and SUMO2 isoforms. These structures reveal a minimal complex interface and elucidate the molecular basis for SENP5’s preference for the SUMO2 isoform. This preference can be attributed to a basic patch surrounding SENP5 Arg624 at the interface. Swapping mutagenesis and structural analysis demonstrate that Arg624 is favorably oriented to interact with Asp63 in SUMO2/3, while its interaction with the equivalent Glu67 in SUMO1 is less favorable. These results suggest that subtle structural differences within SUMO isoforms can significantly influence their deconjugation by SENP enzymes, opening new avenues for exploring the regulation of SUMOylation in various cellular processes and for developing therapeutic agents targeting SUMOylation pathways.

Suggested Citation

  • Lucía Sánchez-Alba & Li Ying & Matthew D. Maletic & Anna Bolòs & Helena Borràs-Gas & Bing Liu & Nathalia Varejão & Virginia Amador & Monique P. C. Mulder & David Reverter, 2025. "Structural basis for the human SENP5’s SUMO isoform discrimination," Nature Communications, Nature, vol. 16(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60029-4
    DOI: 10.1038/s41467-025-60029-4
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    References listed on IDEAS

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    1. Laura A. Claessens & Matty Verlaan-de Vries & Ilona J. Graaf & Alfred C. O. Vertegaal, 2023. "SENP6 regulates localization and nuclear condensation of DNA damage response proteins by group deSUMOylation," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    2. Shyr-Jiann Li & Mark Hochstrasser, 1999. "A new protease required for cell-cycle progression in yeast," Nature, Nature, vol. 398(6724), pages 246-251, March.
    3. Ying Li & Nathalia Varejão & David Reverter, 2022. "Structural basis for the SUMO protease activity of the atypical ubiquitin-specific protease USPL1," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    4. Frauke Liebelt & Nicolette S. Jansen & Sumit Kumar & Ekaterina Gracheva & Laura A. Claessens & Matty Verlaan-de Vries & Edwin Willemstein & Alfred C. O. Vertegaal, 2019. "The poly-SUMO2/3 protease SENP6 enables assembly of the constitutive centromere-associated network by group deSUMOylation," Nature Communications, Nature, vol. 10(1), pages 1-18, December.
    5. Weihai Liu & Yun Wang & Luiz H. M. Bozi & Patrick D. Fischer & Mark P. Jedrychowski & Haopeng Xiao & Tao Wu & Narek Darabedian & Xiadi He & Evanna L. Mills & Nils Burger & Sanghee Shin & Anita Reddy &, 2023. "Lactate regulates cell cycle by remodelling the anaphase promoting complex," Nature, Nature, vol. 616(7958), pages 790-797, April.
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