Toward a molecular understanding of metal transport by P(1B)-type ATPases.

The P(1B) family of P-type ATPases couples the transport of cytoplasmic transition metals across biological membranes to the hydrolysis of ATP. These ubiquitous transporters function in maintaining cytoplasmic metal quotas and in the assembly of metalloproteins, and have been classified into subfamilies (P(1B-1)-P(1B-5)) on the basis of their transported substrates (Cu(+), Zn(2+), Cu(2+), and Co(2+)) and signature sequences in their transmembrane segments. In addition, each subgroup presents a characteristic membrane topology and specific regulatory cytoplasmic metal-binding domains. In recent years, significant major aspects of their transport mechanism have been described, including the stoichiometry of transport and the delivery of substrates to transport sites by metallochaperones. Toward understanding their structure, the metal coordination by transport sites has been characterized for Cu(+) and Zn(2+)-ATPases. In addition, atomic resolution structures have been determined, providing key insight into the elements that enable transition metal transport. Because the Cu(+)-transporting ATPases are found in humans and are linked to disease, this subfamily has been the focus of intense study. As a result, significant progress has been made toward understanding Cu(+)-ATPase function on the molecular level, using both the human proteins and the bacterial homologs, most notably the CopA proteins from Archaeoglobus fulgidus, Bacillus subtilis, and Thermotoga maritima. This chapter thus focuses on the mechanistic and structural information obtained by studying these latter Cu(+)-ATPases, with some consideration of how these aspects might differ for the other subfamilies of P(1B)-ATPases.