Structure of the ArsA ATPase: the catalytic subunit of a heavy metal resistance pump

Active extrusion is a common mechanism underlying detoxification of heavy m etals, drugs and antibiotics in bacteria, protozoa and mammals. In Escheric hia coli, the ArsAB pump provides resistance to arsenite and antimonite. Th is pump consists of a soluble ATPase (ArsA) and a membrane channel (ArsB), ArsA contains two nucleotide-binding sites (NBSs) and a binding site for ar senic or antimony. Binding of metalloids stimulates ATPase activity. The cr ystal structure of ArsA reveals that both NBSs and the metal-binding site a re located at the interface between two homologous domains. A short stretch of residues connecting the metal-binding site to the NBSs provides a signa l transduction pathway that conveys information on metal occupancy to the A TP hydrolysis sites. Based on these structural features, we propose that th e metal-binding site is involved directly in the process of vectorial trans location of arsenite or antimonite across the membrane. The relative positi ons of the NBS and the inferred mechanism of allosteric activation of ArsA provide a useful model for the interaction of the catalytic domains in othe r transport ATPases.