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Structures of UBA6 explain its dual specificity for ubiquitin and FAT10

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  • Ngoc Truongvan

    (University of Würzburg
    Moffitt Cancer Center)

  • Shurong Li

    (University of Würzburg)

  • Mohit Misra

    (University of Würzburg
    Goethe University Faculty of Medicine
    Goethe University Frankfurt, Riedberg Campus)

  • Monika Kuhn

    (University of Würzburg)

  • Hermann Schindelin

    (University of Würzburg)

Abstract

The covalent modification of target proteins with ubiquitin or ubiquitin-like modifiers is initiated by E1 activating enzymes, which typically transfer a single modifier onto cognate conjugating enzymes. UBA6 is an unusual E1 since it activates two highly distinct modifiers, ubiquitin and FAT10. Here, we report crystal structures of UBA6 in complex with either ATP or FAT10. In the UBA6-FAT10 complex, the C-terminal domain of FAT10 binds to where ubiquitin resides in the UBA1-ubiquitin complex, however, a switch element ensures the alternate recruitment of either modifier. Simultaneously, the N-terminal domain of FAT10 interacts with the 3-helix bundle of UBA6. Site-directed mutagenesis identifies residues permitting the selective activation of either ubiquitin or FAT10. These results pave the way for studies investigating the activation of either modifier by UBA6 in physiological and pathophysiological settings.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32040-6
    DOI: 10.1038/s41467-022-32040-6
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    References listed on IDEAS

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    1. Annette Aichem & Christiane Pelzer & Sebastian Lukasiak & Birte Kalveram & Paul W. Sheppard & Neha Rani & Gunter Schmidtke & Marcus Groettrup, 2010. "USE1 is a bispecific conjugating enzyme for ubiquitin and FAT10, which FAT10ylates itself in cis," Nature Communications, Nature, vol. 1(1), pages 1-10, December.
    2. Jianping Jin & Xue Li & Steven P. Gygi & J. Wade Harper, 2007. "Dual E1 activation systems for ubiquitin differentially regulate E2 enzyme charging," Nature, Nature, vol. 447(7148), pages 1135-1138, June.
    3. 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.
    4. Michael W. Lake & Margot M. Wuebbens & K. V. Rajagopalan & Hermann Schindelin, 2001. "Mechanism of ubiquitin activation revealed by the structure of a bacterial MoeB–MoaD complex," Nature, Nature, vol. 414(6861), pages 325-329, November.
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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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