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.
Highlights
The post-translational modification AMPylation, previously referred to as adenylylation, was first discovered by Earl Stadtman et al in the 1960s when he observed that a tyrosine residue of Escherichia coli glutamine synthetase was modified with AMP (Brown et al, 1971)
Concluding remarks The role of AMPylation is in its infancy and many questions about the nature and diversity of this post-translational modification remain to be answered
Bacterial AMPylators have shown a preference for GTPase substrates, but no biologically relevant data supports GTPases as substrates for eukaryotic Fic domain-containing proteins (Worby et al, 2009)
Summary
The post-translational modification AMPylation, previously referred to as adenylylation, was first discovered by Earl Stadtman et al in the 1960s when he observed that a tyrosine residue of Escherichia coli glutamine synthetase was modified with AMP (Brown et al, 1971). It is characterized by a conserved G-X11-D-X-D motif, of which the aspartate residues have been shown to be essential for the AMPylation activity (Figure 1B) (Jiang et al, 2007a; Muller et al, 2010) This domain has been identified in more than 1,400 bacterial proteins among 685 bacterial species, of which the large majority are proteobacteria (Finn et al, 2010). AMPylators in pathogenicity Secretion systems are often used by Gram negative bacterial species to translocate virulence factors, called effectors, into eukaryotic cells These proteins typically subvert cellular processes during infection by locking the target into an active or inactive state, often by mimicking a normal cellular signaling mechanism. Modification by glucosylation or Frontiers in Microbiology | Cellular and Infection Microbiology
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