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

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.
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Simon Veyron, Giulia Oliva, Monica Rolando, Carmen Buchrieser, Gerald Peyroche, et al.. A Ca2+-regulated deAMPylation switch in human and bacterial FIC proteins. Nature Communications, Nature Publishing Group, 2019, 10 (1), pp.1142. ⟨10.1038/s41467-019-09023-1⟩. ⟨hal-02086613⟩

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