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

Luke A. Perera (), Steffen Preissler, Nathan R. Zaccai, Sylvain Prévost, Juliette M. Devos, Michael Haertlein and David Ron ()
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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

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-25076-7

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