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Specificity of AMPylation of the human chaperone BiP is mediated by TPR motifs of FICD

Author

Listed:
  • Joel Fauser

    (University Medical Center Hamburg-Eppendorf (UKE)
    Technical University of Munich)

  • Burak Gulen

    (University Medical Center Hamburg-Eppendorf (UKE)
    Technical University of Munich)

  • Vivian Pogenberg

    (University Medical Center Hamburg-Eppendorf (UKE))

  • Christian Pett

    (Umeå University)

  • Danial Pourjafar-Dehkordi

    (Technical University of Munich)

  • Christoph Krisp

    (University Medical Center Hamburg-Eppendorf (UKE))

  • Dorothea Höpfner

    (University Medical Center Hamburg-Eppendorf (UKE)
    Technical University of Munich)

  • Gesa König

    (University Medical Center Hamburg-Eppendorf (UKE))

  • Hartmut Schlüter

    (University Medical Center Hamburg-Eppendorf (UKE))

  • Matthias J. Feige

    (Technical University of Munich
    Technical University of Munich)

  • Martin Zacharias

    (Technical University of Munich)

  • Christian Hedberg

    (Umeå University)

  • Aymelt Itzen

    (University Medical Center Hamburg-Eppendorf (UKE)
    Technical University of Munich
    University Medical Center Hamburg-Eppendorf (UKE))

Abstract

To adapt to fluctuating protein folding loads in the endoplasmic reticulum (ER), the Hsp70 chaperone BiP is reversibly modified with adenosine monophosphate (AMP) by the ER-resident Fic-enzyme FICD/HYPE. The structural basis for BiP binding and AMPylation by FICD has remained elusive due to the transient nature of the enzyme-substrate-complex. Here, we use thiol-reactive derivatives of the cosubstrate adenosine triphosphate (ATP) to covalently stabilize the transient FICD:BiP complex and determine its crystal structure. The complex reveals that the TPR-motifs of FICD bind specifically to the conserved hydrophobic linker of BiP and thus mediate specificity for the domain-docked conformation of BiP. Furthermore, we show that both AMPylation and deAMPylation of BiP are not directly regulated by the presence of unfolded proteins. Together, combining chemical biology, crystallography and biochemistry, our study provides structural insights into a key regulatory mechanism that safeguards ER homeostasis.

Suggested Citation

  • Joel Fauser & Burak Gulen & Vivian Pogenberg & Christian Pett & Danial Pourjafar-Dehkordi & Christoph Krisp & Dorothea Höpfner & Gesa König & Hartmut Schlüter & Matthias J. Feige & Martin Zacharias & , 2021. "Specificity of AMPylation of the human chaperone BiP is mediated by TPR motifs of FICD," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22596-0
    DOI: 10.1038/s41467-021-22596-0
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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.
    2. Marietta S. Kaspers & Vivian Pogenberg & Christian Pett & Stefan Ernst & Felix Ecker & Philipp Ochtrop & Michael Groll & Christian Hedberg & Aymelt Itzen, 2023. "Dephosphocholination by Legionella effector Lem3 functions through remodelling of the switch II region of Rab1b," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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