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Active site remodelling accompanies thioester bond formation in the SUMO E1

Author

Listed:
  • Shaun K. Olsen

    (Structural Biology and,)

  • Allan D. Capili

    (Structural Biology and,)

  • Xuequan Lu

    (Molecular Pharmacology and Chemistry Programs, Sloan-Kettering Institute, New York, New York 10065, USA)

  • Derek S. Tan

    (Molecular Pharmacology and Chemistry Programs, Sloan-Kettering Institute, New York, New York 10065, USA)

  • Christopher D. Lima

    (Structural Biology and,)

Abstract

E1 enzymes activate ubiquitin (Ub) and ubiquitin-like (Ubl) proteins in two steps by carboxy-terminal adenylation and thioester bond formation to a conserved catalytic cysteine in the E1 Cys domain. The structural basis for these intermediates remains unknown. Here we report crystal structures for human SUMO E1 in complex with SUMO adenylate and tetrahedral intermediate analogues at 2.45 and 2.6 Å, respectively. These structures show that side chain contacts to ATP·Mg are released after adenylation to facilitate a 130 degree rotation of the Cys domain during thioester bond formation that is accompanied by remodelling of key structural elements including the helix that contains the E1 catalytic cysteine, the crossover and re-entry loops, and refolding of two helices that are required for adenylation. These changes displace side chains required for adenylation with side chains required for thioester bond formation. Mutational and biochemical analyses indicate these mechanisms are conserved in other E1s.

Suggested Citation

  • Shaun K. Olsen & Allan D. Capili & Xuequan Lu & Derek S. Tan & Christopher D. Lima, 2010. "Active site remodelling accompanies thioester bond formation in the SUMO E1," Nature, Nature, vol. 463(7283), pages 906-912, February.
    • Handle: RePEc:nat:nature:v:463:y:2010:i:7283:d:10.1038_nature08765
    DOI: 10.1038/nature08765
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    Cited by:

    1. 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.
    2. Ngoc Truongvan & Shurong Li & Mohit Misra & Monika Kuhn & Hermann Schindelin, 2022. "Structures of UBA6 explain its dual specificity for ubiquitin and FAT10," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    3. Lingmin Yuan & Fei Gao & Zongyang Lv & Digant Nayak & Anindita Nayak & Priscila dos Santos Bury & Kristin E. Cano & Lijia Jia & Natalia Oleinik & Firdevs Cansu Atilgan & Besim Ogretmen & Katelyn M. Wi, 2022. "Crystal structures reveal catalytic and regulatory mechanisms of the dual-specificity ubiquitin/FAT10 E1 enzyme Uba6," Nature Communications, Nature, vol. 13(1), pages 1-14, December.

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