AMPylation: something old is new again

Abstract

The post-translational modification AMPylation is emerging as a significant regulatory mechanism in both prokaryotic and eukaryotic biology. This process involves the covalent addition of an adenosine monophosphate to a protein resulting in a modified protein with altered activity. Proteins capable of catalyzing AMPylation, termed AMPylators, are comparable to kinases in that they both hydrolyze ATP and reversibly transfer a part of this primary metabolite to a hydroxyl side chain of the protein substrate. To date, only four AMPylators have been characterized, though many more potential candidates have been identified through amino acid sequence analysis and preliminary in vitro studies. This modification was first discovered over 40 years ago by Earl Stadtman and colleagues through the modification of glutamine synthetase by adenylyl transferase; however research into this mechanism has only just been reenergized by the studies on bacterial effectors. New AMPylators were revealed due to the discovery that a bacterial effector having a conserved Fic domain transfers an AMP group to protein substrates. Current research focuses on identifying and characterizing various types of AMPylators homologous to Fic domains and adenylyl transferase domains and their respective substrates. While all AMPylators characterized thus far are bacterial proteins, the conservation of the Fic domain in eukaryotic organisms suggests that AMPylation is omnipresent in various forms of life and has significant impact on a wide range of regulatory processes.

Characterization of Enzymes from Legionella pneumophila Involved in Reversible Adenylylation of Rab1 Protein

“…As an explanation of the ready acceptance of the GDP-bound form of AMP-Rab1 by SidD, AMP-Rab1⅐GDP, might adopt an active-like conformation of the switch II region as the crystal structure of AMP-Rab1b⅐GppNHp (PDB ID 3NKV) (18) showed a stacking interaction of the adenosine and Phe 45 , and this interaction might also occur in AMP-Rab1⅐GDP. This (Table 4).…”

HypE-specific Nanobodies as Tools to Modulate HypE-mediated Target AMPylation

“…Eukaryotes, including Caenorhabditis elegans, Drosophila melanogaster, Mus musculus, and Homo sapiens, encode at least one Fic protein each, with the exception of most fungi, which contain no known AMPylases (16,17). The Drosophila Fic protein, referred to as CG9523 or dFic, possesses auto-AMPylation activity in vitro; this activity is diminished upon mutation of the conserved histidine residue within the Fic motif (18).…”

Unfolded Protein Response-regulated Drosophila Fic (dFic) Protein Reversibly AMPylates BiP Chaperone during Endoplasmic Reticulum Homeostasis

“…AMPylation is a posttranslational modification involving a covalent attachment of an AMP moiety from ATP to hydroxyl side chains of target substrates (1). This modification was first discovered in Escherichia coli in the 1960s from a study characterizing glutamine synthetase (GS) 2 adenylyl transferase (2, 3).…”