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

Joel Fauser, Burak Gulen, Vivian Pogenberg, Christian Pett, Danial Pourjafar-Dehkordi, Christoph Krisp, Dorothea Höpfner, Gesa König, Hartmut Schlüter, Matthias J. Feige, Martin Zacharias, Christian Hedberg () and Aymelt Itzen ()
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Joel Fauser: University Medical Center Hamburg-Eppendorf (UKE)
Burak Gulen: University Medical Center Hamburg-Eppendorf (UKE)
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)
Gesa König: University Medical Center Hamburg-Eppendorf (UKE)
Hartmut Schlüter: University Medical Center Hamburg-Eppendorf (UKE)
Matthias J. Feige: Technical University of Munich
Martin Zacharias: Technical University of Munich
Christian Hedberg: Umeå University
Aymelt Itzen: University Medical Center Hamburg-Eppendorf (UKE)

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: 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.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22596-0

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DOI: 10.1038/s41467-021-22596-0

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