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Structures of a deAMPylation complex rationalise the switch between antagonistic catalytic activities of FICD

Author

Listed:
  • Luke A. Perera

    (University of Cambridge)

  • Steffen Preissler

    (University of Cambridge)

  • Nathan R. Zaccai

    (University of Cambridge)

  • Sylvain Prévost

    (Institut Laue-Langevin)

  • Juliette M. Devos

    (Institut Laue-Langevin)

  • Michael Haertlein

    (Institut Laue-Langevin)

  • David Ron

    (University of Cambridge)

Abstract

The endoplasmic reticulum (ER) Hsp70 chaperone BiP is regulated by AMPylation, a reversible inactivating post-translational modification. Both BiP AMPylation and deAMPylation are catalysed by a single ER-localised enzyme, FICD. Here we present crystallographic and solution structures of a deAMPylation Michaelis complex formed between mammalian AMPylated BiP and FICD. The latter, via its tetratricopeptide repeat domain, binds a surface that is specific to ATP-state Hsp70 chaperones, explaining the exquisite selectivity of FICD for BiP’s ATP-bound conformation both when AMPylating and deAMPylating Thr518. The eukaryotic deAMPylation mechanism thus revealed, rationalises the role of the conserved Fic domain Glu234 as a gatekeeper residue that both inhibits AMPylation and facilitates hydrolytic deAMPylation catalysed by dimeric FICD. These findings point to a monomerisation-induced increase in Glu234 flexibility as the basis of an oligomeric state-dependent switch between FICD’s antagonistic activities, despite a similar mode of engagement of its two substrates — unmodified and AMPylated BiP.

Suggested Citation

  • Luke A. Perera & Steffen Preissler & Nathan R. Zaccai & Sylvain Prévost & Juliette M. Devos & Michael Haertlein & David Ron, 2021. "Structures of a deAMPylation complex rationalise the switch between antagonistic catalytic activities of FICD," Nature Communications, Nature, vol. 12(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-25076-7
    DOI: 10.1038/s41467-021-25076-7
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    Cited by:

    1. Dandan Wang & Lingfang Zhu & Xiangkai Zhen & Daoyan Yang & Changfu Li & Yating Chen & Huannan Wang & Yichen Qu & Xiaozhen Liu & Yanling Yin & Huawei Gu & Lei Xu & Chuanxing Wan & Yao Wang & Songying O, 2022. "A secreted effector with a dual role as a toxin and as a transcriptional factor," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

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