Abstract
Protein AMPylation refers to the covalent attachment of an AMP moiety to the amino acid side chains of target proteins using ATP as nucleotide donor. This process is catalysed by dedicated AMP transferases, called AMPylases. Since this initial discovery, several research groups have identified AMPylation as a critical post-translational modification relevant to normal and pathological cell signalling in both bacteria and metazoans. Bacterial AMPylases are abundant enzymes that either regulate the function of endogenous bacterial proteins or are translocated into host cells to hijack host cell signalling processes. By contrast, only two classes of metazoan AMPylases have been identified so far: enzymes containing a conserved filamentation induced by cAMP (Fic) domain (Fic AMPylases), which primarily modify the ER-resident chaperone BiP, and SelO, a mitochondrial AMPylase involved in redox signalling. In this review, we compare and contrast bacterial and metazoan Fic and non-Fic AMPylases, and summarize recent technological and conceptual developments in the emerging field of AMPylation.
Highlights
Post-translational modifications (PTMs) may regulate proteins by activating or repressing protein function, allowing protein oligo- or monomerization or installing binding sites for allosteric interactors
The authors found that filamentation induced by cAMP (Fic) domain-mediated AMPylation is not responsible 5 for the interaction between Bartonella henselae effector protein C (BepC) and GEF-H1 as a BepC quadruple mutant harbouring mutations in the active site (H146A, K150A, R154A and R157A) of the Fic motif (HxFxKGNGRxxR) was able to trigger stress fibre formation as effectively as WT BepC. This observation indicates that this non-canonical BepC Fic domain is involved in a non-catalytic role and is the first example to our knowledge where a bacterial fic domain-containing (FicD) effector protein induces host cell killing without AMPylating any host target proteins [63,64]
These FicD-type AMPylases exhibit remarkable similarity in their structural architecture: an N-terminal transmembrane domain (TM) responsible for ER localization of these enzymes and anchoring to the ER luminal membrane, followed by one or two tetratricopeptide repeats (TPRs) involved in substrate recognition and specificity, and a C-terminal Fic domain linked to the TPRs by a less-conserved α-helical linker required for mediating allosteric conformational changes [5,6,56]
Summary
Post-translational modifications (PTMs) may regulate proteins by activating or repressing protein function, allowing protein oligo- or monomerization or installing binding sites for allosteric interactors. AMPylation, referred to as adenylylation, is conferred by AMPylases, which belong to four distinct protein families: fic domain-containing (FicD) enzymes, selenoproteins (SelO), glutamine synthetase adenylyl transferases (GS-ATase) and DrrA. These enzymes catalyse the formation of a covalent bond between the phosphate group of AMP and an accessible Ser, Thr or Tyr hydroxyl group of the target protein. In contrast to FicD enzymes, GS-ATase, DrrA and the eukaryotic pseudokinase, SelO, do not contain the conserved FicD, and employ a catalytic mechanism distinct from FicD AMPylases (figure 1) These AMPylases, together with putative additional AMPylases and deAMPylases, define the protein AMPylome, or the universe of AMPylated proteins. We will not discuss bacterial AMPylases that modify endogenous substrates which are discussed in excellent reviews by Woolery et al [10] and Casey et al [11]
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