The structure and function of heavy metal transport P1B-ATPases

Abstract

P_1B-type ATPases transport heavy metals (Cu⁺, Cu²⁺, Zn²⁺, Co²⁺, Cd²⁺, Pb²⁺) across membranes. Present in most organisms, they are key elements for metal homeostasis. P_1B-type ATPases contain 6-8 transmembrane fragments carrying signature sequences in segments flanking the large ATP binding cytoplasmic loop. These sequences made possible the differentiation of at least four P_1B-ATPase subgroups with distinct metal selectivity: P_1B-1: Cu⁺, P_1B-2: Zn²⁺, P_1B-3: Cu²⁺, P_1B-4: Co²⁺. Mutagenesis of the invariant transmembrane Cys in H6, Asn and Tyr in H7 and Met and Ser in H8 of the Archaeoglobus fulgidus Cu⁺-ATPase has revealed that their side chains likely coordinate the metals during transport and constitute a central unique component of these enzymes. The structure of various cytoplasmic domains has been solved. The overall structure of those involved in enzyme phosphorylation (P-domain), nucleotide binding (N-domain) and energy transduction (A-domain), appears similar to those described for the SERCA Ca²⁺-ATPase. However, they show different features likely associated with singular functions of these proteins. Many P_1B-type ATPases, but not all of them, also contain a diverse arrangement of cytoplasmic metal binding domains (MBDs). In spite of their structural differences, all N- and C-terminal MBDs appear to control the enzyme turnover rate without affecting metal binding to transmembrane transport sites. In addition, eukaryotic Cu⁺-ATPases have multiple N-MBD regions that participate in the metal dependent targeting and localization of these proteins. The current knowledge of structure-function relationships among the different P_1B-ATPases allows for a description of selectivity, regulation and transport mechanisms. Moreover, it provides a framework to understand mutations in human Cu⁺-ATPases (ATP7A and ATP7B) that lead to Menkes and Wilson diseases.