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Basis for a ubiquitin-like protein thioester switch toggling E1–E2 affinity

Author

Listed:
  • Danny T. Huang

    (Howard Hughes Medical Institute
    St Jude Children’s Research Hospital)

  • Harold W. Hunt

    (St Jude Children’s Research Hospital)

  • Min Zhuang

    (St Jude Children’s Research Hospital
    University of Tennessee Health Sciences Center)

  • Melanie D. Ohi

    (Harvard Medical School)

  • James M. Holton

    (Lawrence Berkeley National Laboratory University of California)

  • Brenda A. Schulman

    (Howard Hughes Medical Institute
    St Jude Children’s Research Hospital
    University of Tennessee Health Sciences Center)

Abstract

Ubiquitin-like proteins (UBLs) are conjugated by dynamic E1–E2–E3 enzyme cascades. E1 enzymes activate UBLs by catalysing UBL carboxy-terminal adenylation, forming a covalent E1˜UBL thioester intermediate, and generating a thioester-linked E2˜UBL product, which must be released for subsequent reactions. Here we report the structural analysis of a trapped UBL activation complex for the human NEDD8 pathway, containing NEDD8’s heterodimeric E1 (APPBP1–UBA3), two NEDD8s (one thioester-linked to E1, one noncovalently associated for adenylation), a catalytically inactive E2 (Ubc12), and MgATP. The results suggest that a thioester switch toggles E1–E2 affinities. Two E2 binding sites depend on NEDD8 being thioester-linked to E1. One is unmasked by a striking E1 conformational change. The other comes directly from the thioester-bound NEDD8. After NEDD8 transfer to E2, reversion to an alternate E1 conformation would facilitate release of the E2˜NEDD8 thioester product. Thus, transferring the UBL’s thioester linkage between successive conjugation enzymes can induce conformational changes and alter interaction networks to drive consecutive steps in UBL cascades.

Suggested Citation

  • Danny T. Huang & Harold W. Hunt & Min Zhuang & Melanie D. Ohi & James M. Holton & Brenda A. Schulman, 2007. "Basis for a ubiquitin-like protein thioester switch toggling E1–E2 affinity," Nature, Nature, vol. 445(7126), pages 394-398, January.
    • Handle: RePEc:nat:nature:v:445:y:2007:i:7126:d:10.1038_nature05490
    DOI: 10.1038/nature05490
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    Cited by:

    1. Martin Schröder & Martin Renatus & Xiaoyou Liang & Fabian Meili & Thomas Zoller & Sandrine Ferrand & Francois Gauter & Xiaoyan Li & Frederic Sigoillot & Scott Gleim & Therese-Marie Stachyra & Jason R., 2024. "DCAF1-based PROTACs with activity against clinically validated targets overcoming intrinsic- and acquired-degrader resistance," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    2. Mohammad Afsar & GuanQun Liu & Lijia Jia & Eliza A. Ruben & Digant Nayak & Zuberwasim Sayyad & Priscila dos Santos Bury & Kristin E. Cano & Anindita Nayak & Xiang Ru Zhao & Ankita Shukla & Patrick Sun, 2023. "Cryo-EM structures of Uba7 reveal the molecular basis for ISG15 activation and E1-E2 thioester transfer," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

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