Structurally diverse C-terminal accessory domains in type I ABC importers reveal distinct regulatory mechanisms

Abstract

ATP-binding cassette (ABC) transporters are critical for cellular processes, facilitating the transport of various substrates across membranes by harnessing ATP hydrolysis. These transporters are divided into importers and exporters, with importers playing key roles in nutrient uptake and bacterial virulence. Despite their therapeutic potential as drug targets, the regulatory mechanisms governing ABC importers remain poorly understood. ABC importers often possess additional cytosolic C-terminal accessory domains fused to nucleotide-binding domains (NBDs). These accessory domains, also referred to as C-terminal regulatory domains (CRDs), modulate transport activity by inhibiting NBD dimerization or ATP hydrolysis in response to environmental cues, thus regulating substrate transport. The diversity in CRD folds, architectures, and regulatory mechanisms adds additional complexity to transporter regulation. This review explores the current understanding of C-terminal accessory domains in type I ABC importers, highlighting their contributions to transporter function.