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Structural basis for UFM1 transfer from UBA5 to UFC1

Author

Listed:
  • Manoj Kumar

    (The Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School)

  • Prasanth Padala

    (The Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School
    University of Otago)

  • Jamal Fahoum

    (The Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School)

  • Fouad Hassouna

    (The Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School)

  • Tomer Tsaban

    (Institute for Medical Research Israel-Canada, Faculty of Medicine, The Hebrew University of Jerusalem)

  • Guy Zoltsman

    (Weizmann Institute of Sciences)

  • Sayanika Banerjee

    (The Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School)

  • Einav Cohen-Kfir

    (The Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School)

  • Moshe Dessau

    (Bar-Ilan University)

  • Rina Rosenzweig

    (Weizmann Institute of Sciences)

  • Michail N. Isupov

    (University of Exeter)

  • Ora Schueler-Furman

    (Institute for Medical Research Israel-Canada, Faculty of Medicine, The Hebrew University of Jerusalem)

  • Reuven Wiener

    (The Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School)

Abstract

Ufmylation is a post-translational modification essential for regulating key cellular processes. A three-enzyme cascade involving E1, E2 and E3 is required for UFM1 attachment to target proteins. How UBA5 (E1) and UFC1 (E2) cooperatively activate and transfer UFM1 is still unclear. Here, we present the crystal structure of UFC1 bound to the C-terminus of UBA5, revealing how UBA5 interacts with UFC1 via a short linear sequence, not observed in other E1-E2 complexes. We find that UBA5 has a region outside the adenylation domain that is dispensable for UFC1 binding but critical for UFM1 transfer. This region moves next to UFC1’s active site Cys and compensates for a missing loop in UFC1, which exists in other E2s and is needed for the transfer. Overall, our findings advance the understanding of UFM1’s conjugation machinery and may serve as a basis for the development of ufmylation inhibitors.

Suggested Citation

  • Manoj Kumar & Prasanth Padala & Jamal Fahoum & Fouad Hassouna & Tomer Tsaban & Guy Zoltsman & Sayanika Banerjee & Einav Cohen-Kfir & Moshe Dessau & Rina Rosenzweig & Michail N. Isupov & Ora Schueler-F, 2021. "Structural basis for UFM1 transfer from UBA5 to UFC1," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-25994-6
    DOI: 10.1038/s41467-021-25994-6
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    Cited by:

    1. Iona Wallace & Kheewoong Baek & J. Rajan Prabu & Ronnald Vollrath & Susanne Gronau & Brenda A. Schulman & Kirby N. Swatek, 2023. "Insights into the ISG15 transfer cascade by the UBE1L activating enzyme," Nature Communications, Nature, vol. 14(1), pages 1-13, December.

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