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A Ca 2+ -regulated deAMPylation switch in human and bacterial FIC proteins.
- Source :
-
Nature communications [Nat Commun] 2019 Mar 08; Vol. 10 (1), pp. 1142. Date of Electronic Publication: 2019 Mar 08. - Publication Year :
- 2019
-
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 Mg <superscript>2+</superscript> and Ca <superscript>2+</superscript> control AMPylation and deAMPylation differentially without a conformational change. Remarkably, Ca <superscript>2+</superscript> 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.
- Subjects :
- Adenosine Monophosphate chemistry
Animals
Bacterial Proteins genetics
Bacterial Proteins metabolism
Binding Sites
Biocatalysis
Calcium chemistry
Cations, Divalent
Chemokine CCL7 genetics
Chemokine CCL7 metabolism
Cloning, Molecular
Crystallography, X-Ray
Endoplasmic Reticulum Chaperone BiP
Enterococcus faecalis genetics
Enterococcus faecalis metabolism
Escherichia coli genetics
Escherichia coli metabolism
Gene Expression
Heat-Shock Proteins genetics
Heat-Shock Proteins metabolism
Humans
Magnesium chemistry
Magnesium metabolism
Mice
Models, Molecular
Protein Binding
Protein Conformation, alpha-Helical
Protein Conformation, beta-Strand
Protein Interaction Domains and Motifs
Recombinant Proteins chemistry
Recombinant Proteins genetics
Recombinant Proteins metabolism
Substrate Specificity
Adenosine Monophosphate metabolism
Bacterial Proteins chemistry
Calcium metabolism
Chemokine CCL7 chemistry
Heat-Shock Proteins chemistry
Protein Processing, Post-Translational
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 10
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 30850593
- Full Text :
- https://doi.org/10.1038/s41467-019-09023-1