CNRS and ENS Paris-Saclay, Laboratory of Biology and Pharmacology, Cachan A Ca2+-regulated deAMPylation switch in human and bacterial FIC proteins Nat Commun. 2019 Mar 8;10(1):1142. doi: 10.1038/s41467-019-09023-1 Veyron S, Oliva G, Rolando M, Buchrieser C, Peyroche G, Cherfils J
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Simon Veyron, 30 years old, completed a Master's degree in "Biomolecular Engineering" at Paris-Saclay University. In 2017, Simon Veyron obtained a PhD entitled "Structure and function of bacterial proteins with FIC domain" and carried out in the Laboratory of Biology and Applied Pharmacology (LBPA, CNRS and Ecole Normale Supérieure, Paris-Saclay) under the supervision of Jacqueline Cherfils. His main area of interest is structural biochemistry using X-ray crystallography. In the selected article published in Nature Communications, Simon Veyron and collaborators have shown that two AMPylases of the FIC family, one bacterial and the other human, are directly regulated by calcium. Importantly, they suggest that these enzymes have feature of an enzymatic Ca2+ sensor, an hallmark of the ER stress with implications in therapeutic strategies against diseases that involve the UPR. Simon Veyron is currently working in Jean-François Trempe's « Parkinson's disease and PINK1 » team at McGill University in Montreal on the structure of proteins implicated in some forms of Parkinson's disease.
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Simon VEYRON
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Abstract
FIC proteins regulate molecular processes from bacteria to humans by catalyzing post-translational modifications (PTM), the most frequent being the addition of AMP orAMPylation. 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.
