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Nat Commun. 2019 Mar 8;10(1):1142. doi: 10.1038/s41467-019-09023-1.

A Ca2+-regulated deAMPylation switch in human and bacterial FIC proteins.

Author information

1
CNRS and Ecole normale supérieure Paris-Saclay, Laboratoire de Biologie et Pharmacologie Appliquée, 61 Avenue du Président Wilson, 94235, Cachan CEDEX, France.
2
Institut Pasteur and CNRS UMR 3525, Biologie des Bactéries Intracellulaires, 25-28 Rue du Dr Roux, 75015, Paris, France.
3
Sorbonne Université, Collège doctoral, 75005, Paris, France.
4
CNRS and Ecole normale supérieure Paris-Saclay, Laboratoire de Biologie et Pharmacologie Appliquée, 61 Avenue du Président Wilson, 94235, Cachan CEDEX, France. jacqueline.cherfils@ens-paris-saclay.fr.

Abstract

FIC proteins regulate molecular processes from bacteria to humans by catalyzing post-translational modifications (PTM), the most frequent being the addition of AMP or AMPylation. In many AMPylating FIC proteins, a structurally conserved glutamate represses AMPylation and, in mammalian FICD, also supports deAMPylation of BiP/GRP78, a key chaperone of the unfolded protein response. Currently, a direct signal regulating these FIC proteins has not been identified. Here, we use X-ray crystallography and in vitro PTM assays to address this question. We discover that Enterococcus faecalis FIC (EfFIC) catalyzes both AMPylation and deAMPylation and that the glutamate implements a multi-position metal switch whereby Mg2+ and Ca2+ control AMPylation and deAMPylation differentially without a conformational change. Remarkably, Ca2+ concentration also tunes deAMPylation of BiP by human FICD. Our results suggest that the conserved glutamate is a signature of AMPylation/deAMPylation FIC bifunctionality and identify metal ions as diffusible signals that regulate such FIC proteins directly.

PMID:
30850593
PMCID:
PMC6408439
DOI:
10.1038/s41467-019-09023-1
[Indexed for MEDLINE]
Free PMC Article

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