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

DOI: 10.1038/s41467-021-25076-7 DOI Help

Authors: 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)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Communications , VOL 12

State: Published (Approved)
Published: August 2021
Diamond Proposal Number(s): 21426

Open Access Open Access

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.

Journal Keywords: Chaperones; Endoplasmic reticulum; Enzyme mechanisms; Post-translational modifications

Diamond Keywords: Enzymes

Subject Areas: Biology and Bio-materials, Chemistry


Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)

Added On: 11/10/2021 11:25

Documents:
s41467-021-25076-7.pdf

Discipline Tags:

Catalysis Life Sciences & Biotech Structural biology Chemistry Biochemistry

Technical Tags:

Diffraction Macromolecular Crystallography (MX)