Type II toxin-antitoxin loci: The fic family

Abstract

FIC domain containing proteins (Fic proteins) are present in all domains of life but particularly widespread among prokaryotes. FIC domains with a fully conserved HxFx[D/E]GNGRxxR active site motif catalyze adenylylation (also known as AMPylation), the transfer of an adenosine 5′-monophosphate moiety onto target proteins. Adenylylation activity is tightly controlled by an inhibitory α-helix (α inh) that can either be part of the Fic protein (intramolecular inhibition) or encoded on a different polypeptide chain (intermolecular inhibition), the latter constituting a novel class of type II toxin-antitoxin (TA) modules represented by VbhT-VbhA of Bartonella schoenbuchensis and FicT-FicA of Escherichia coli. The helix α inh harbors a [S/T]xxxE[G/N] motif with the conserved glutamate partially obstructing the ATP-binding site and forcing ATP to bind in a catalytically incompetent conformation. Release of inhibition by removal of the antitoxin component or by mutation of the conserved glutamate in α inh converts Fic proteins into toxins that severely impair bacterial growth.