Specificity of AMPylation of the Human Chaperone BiP is Mediated by TPR Motifs of FICD

Overview

Journal Nat Commun

Specialty Biology

Date 2021 Apr 24

PMID 33893288

Citations 11

Authors

Joel Fauser

Burak Gulen

Vivian Pogenberg

Christian Pett

Danial Pourjafar-Dehkordi

Christoph Krisp

Dorothea Hopfner

Gesa Konig

Hartmut Schluter

Matthias J Feige

Martin Zacharias

Christian Hedberg

Aymelt Itzen

Affiliations

Soon will be listed here.

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.

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