Structural Basis of Ion Transport in Copper‐Transporting P IB ‐Type ATPases

Authors:
  • VBViktoria Bågenholm
    Viktoria Bågenholm
  • PGPontus Gourdon
    Pontus Gourdon
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Abstract
Maintaining correct copper levels is vital for all cells, as copper is required for a large number of cellular processes, but is also toxic due to its high reactivity. Such regulation is accomplished using a range of processes, including the P IB‐1 ‐subgroup of P‐type ATPases. These primary active transporters exploit ATP to shuttle copper across cellular membranes, either out of the cell or into various organelles for cellular use, such as incorporation into copper‐dependent proteins. The pumping of copper across the membrane follows a conserved scheme, called the Post‐Albers cycle, where the protein cycles through a series of states, from inward‐open (E1) to inward‐occluded (E1P), outward‐open (E2P), and outward‐occluded (E2) and back, coupled to phosphorylation by ATP and dephosphorylation. This is established via a conserved core consisting of three soluble A‐, P‐, and N‐domains, and a transmembrane domain formed by eight membrane‐spanning helices, MA, MB, and M1–M6, as well as a varying number of metal‐binding domains MBDs, which typically are part of the N‐terminus. Copper is delivered to the P IB‐1 ‐transporter from small molecule or protein copper chaperones inside the cytoplasm, likely assisted by an MBD. The metal is then transferred to a methionine of M1 at the membrane interface, which relocates it to two conserved cysteines of the CPC motif in M4. Next, one or two high‐affinity‐binding sites are established in the M‐domain, again utilizing cysteines and methionines. Finally, release is achieved via an outward‐facing exit tunnel lined by methionines. While much of this pathway has been elucidated through determined molecular structures, important questions remain, for example, regarding the number of high‐affinity‐binding sites and the roles of the MBDs. Here, the structural details of the transport of copper through P IB‐1 ‐type ATPases will be described.

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