Biological Diversity and Molecular Plasticity of FIC Domain Proteins

The ubiquitous proteins with FIC (filamentation induced by cyclic AMP) domains use a conserved enzymatic machinery to modulate the activity of various target proteins by posttranslational modification, typically AMPylation. Following intensive study of the general properties of FIC domain catalysis, diverse molecular activities and biological functions of these remarkably versatile proteins are now being revealed. Here, we review the biological diversity of FIC domain proteins and summarize the underlying structure-function relationships. The original and most abundant genuine bacterial FIC domain proteins are toxins that use diverse molecular activities to interfere with bacterial physiology in various, yet ill-defined, biological contexts. Host-targeted virulence factors have evolved repeatedly out of this pool by exaptation of the enzymatic FIC domain machinery for the manipulation of host cell signaling in favor of bacterial pathogens. The single human FIC domain protein HypE (FICD) has a specific function in the regulation of protein stress responses

Adenylylation of Gyrase and Topo IV by FicT Toxins Disrupts Bacterial DNA Topology

Toxin-antitoxin (TA) modules are ubiquitous molecular switches controlling bacterial growth via the release of toxins that inhibit cell proliferation. Most of these toxins interfere with protein translation, but a growing variety of other mechanisms hints at a diversity that is not yet fully appreciated. Here, we characterize a group of FIC domain proteins as toxins of the conserved and abundant FicTA family of TA modules, and we reveal that they act by suspending control of cellular DNA topology. We show that FicTs are enzymes that adenylylate DNA gyrase and topoisomerase IV, the essential bacterial type IIA topoisomerases, at their ATP-binding site. This modification inactivates both targets by blocking their ATPase activity, and, consequently, causes reversible growth arrest due to the knotting, catenation, and relaxation of cellular DNA. Our results give insight into the regulation of DNA topology and highlight the remarkable plasticity of FIC domain proteins