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Moving some metal

SBKB [doi:10.1038/sbkb.2011.32]
Featured Article - August 2011
Short description: The crystal structure of a copper-transporting P1B-type ATPase provides valuable insight into how mutations contribute to Menkes' and Wilson's diseases.

Two human conditions, Menkes' and Wilson's diseases, have both been linked to defects in copper transport by the P1B-type transporters ATP7A and ATP7B, respectively. Additionally, copper transport is of crucial importance for organisms from all kingdoms, as copper is a biologically necessary element that can quickly become toxic as it accumulates. To regulate this, P1B-type transmembrane ATPases use energy from ATP to actively transport copper from the cytoplasm into different cellular organelles or out of the cell, and although there has been some structural analysis of the cytoplasmic domains of P1B-type ATPases, no atomic structure of a complete P1B-type transporter has previously been made available.

The LpCopA structure gives insight into the mechanism of copper transport in P1B-type ATPases. 1

To address the mechanism behind copper transport, and how it is affected by clinical mutations, Nissen and colleagues now report the crystal structure of the P1B-type copper transporter from Legionella pneumophila, LpCopA, at 3.2-Å resolution (PDB 3RFU). The final model presents almost the entire 736-residue protein, although the heavy metal–binding domain (HMBD) could not be completely resolved owing to intrinsic disorder and possible flexibility of that domain in a copper-free state. However, there was continuous low-resolution electron density in the region of the HMBD, allowing the authors to approximate its location and generate a picture of how it may regulate copper transport that is consistent with previously published biochemical and EM data.

Perhaps the most important insight provided by the new LpCopA structure is the ability to generate a model for copper transport from the cytoplasm of L. pneumophila to the periplasm. Examination of the structure revealed a platform, lined by an amphiphilic MB′ helix and a straight M1 transmembrane helix, that encompasses three highly-conserved amino acids. This region may provide a docking site for the HMBD (or another copper chaperone) and the three residues an entry site for copper allowing transport of the copper ion via internal membranous ion-binding sites and an exit site on the periplasmic side of the transporter through an ATPase-coupled mechanism with conformational changes similar to that seen with the calcium transporter SERCA1a.

As a result of the similarity of LpCopA to ATP7A, the authors were also able to map known mutations associated with Menkes' disease to their structure. Most mutations are found in regions that affect various aspects of transporter function, including residues involved in phosphorylation or dephosphorylation, copper entry and exit, intramembranous copper binding and domain interactions. Thus, whereas the clinical manifestations of these mutations may be convergent, the biochemical mechanisms leading to the disease phenotypes are somewhat diverse. Therefore, the insights provided by this structural analysis will undoubtedly aid researchers seeking to improve treatment for both Menkes' and Wilson's diseases.

Steve Mason

References

  1. P. Gourdon et al. Crystal structure of a copper-transporting PIB-type ATPase.
    Nature 475, 59-64 (2011). doi:10.1038/nature10191

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Funded by a grant from the National Institute of General Medical Sciences of the National Institutes of Health