Fic and non-Fic AMPylases: protein AMPylation in metazoans

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.

Fmp40 ampylase regulates cell survival upon oxidative stress by controlling Prx1 and Trx3 oxidation

“…Recently we have reported that the yeast IMS-localized Fmp40 protein, belonging to the highly evolutionarily conserved SelO family, is regulated by its oxidation and reduction 10 . SelO proteins have an AMPylase activity, in which the adenosine monophosphate (AMP) moiety is attached to the threonine, serine, or tyrosine residues in proteins, and are active when they are in a reduced state 11,12 . Fmp40 is the only identified AMPylase in Saccharomyces cerevisiae to date.…”

The AMPylase FIC-1 modulates TGF-β signaling in Caenorhabditis elegans

“…The human AMPylase, FICD, and its C. elegans ortholog, FIC-1, belong to a family of fic domain-containing AMPylases present as a single copy in metazoans ( Truttmann and Ploegh, 2017 ; Casey and Orth, 2018 ; Chatterjee and Truttmann, 2021 ). Fic AMPylases are bi-functional, catalyzing both the addition (AMPylation) and the removal (deAMPylation) of an adenosine monophosphate (AMP) moiety to serine or threonine hydroxyl groups of target proteins using a single active site ( Ham et al, 2014 ; Preissler et al, 2015 , 2017a , b ; Sanyal et al, 2015 ).…”

“…FICD AMPylates and deAMPylates the ER-resident HSP70 family chaperone BiP on Thr518 and Thr356, which serves as a mechanism to regulate client binding and refolding activity of the cellular BiP pool ( Truttmann and Ploegh, 2017 ; Casey and Orth, 2018 ; Chatterjee and Truttmann, 2021 ). Similarly, FIC-1 AMPylates the two presumable functionally redundant C. elegans BiP orthologs HSP-3 and HSP-4 in the ER.…”