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Structural basis for copper transfer by the metallochaperone for the Menkes/Wilson disease proteins

Nature Structural Biology volume 7, pages 766–771 (2000)Cite this article

Abstract

The Hah1 metallochaperone protein is implicated in copper delivery to the Menkes and Wilson disease proteins. Hah1 and the N-termini of its target proteins belong to a family of metal binding domains characterized by a conserved MT/HCXXC sequence motif. The crystal structure of Hah1 has been determined in the presence of Cu(I), Hg(II), and Cd(II). The 1.8 Å resolution structure of CuHah1 reveals a copper ion coordinated by Cys residues from two adjacent Hah1 molecules. The CuHah1 crystal structure is the first of a copper chaperone bound to copper and provides structural support for direct metal ion exchange between conserved MT/HCXXC motifs in two domains. The structures of HgHah1 and CdHah1, determined to 1.75 Å resolution, also reveal metal ion coordination by two MT/HCXXC motifs. An extended hydrogen bonding network, unique to the complex of two Hah1 molecules, stabilizes the metal binding sites and suggests specific roles for several conserved residues. Taken together, the structures provide models for intermediates in metal ion transfer and suggest a detailed molecular mechanism for protein recognition and metal ion exchange between MT/HCXXC containing domains.

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Figure 1: Structure of CuHah1.
Figure 2: Stereo views of the metal binding sites in Hah1 and Atx1.
Figure 3: Hydrogen bonding interactions.
Figure 4: Proposed mechanism of copper transfer between Hah1 and a domain of the Menkes or Wilson protein.

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Acknowledgements

This work was supported by NIH grants to A.C.R. and T.V.O., by an NIH training grant to D.L.H., and by an NIH NRSA Fellowship to A.L.L. Stanford Synchrotron Radiation Laboratory (SSRL) is funded by the Department of Energy, Office of Basic Energy Sciences, and the DND-CAT Synchrotron Research Center at the Advanced Photon Source is supported by the E.I. DuPont de Nemours & Co., The Dow Chemical Company, the NSF, and the State of Illinois.

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  1. Department of Biochemistry, Molecular Biology, and Cell Biology, Northwestern University, Evanston, 60208, Illinois, USA

    Amy K. Wernimont, Audrey L. Lamb, Thomas V. O'Halloran & Amy C. Rosenzweig

  2. Department of Chemistry, Northwestern University, Evanston, 60208, Illinois, USA

    David L. Huffman, Thomas V. O'Halloran & Amy C. Rosenzweig

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  1. Amy K. Wernimont
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Correspondence to Amy C. Rosenzweig.

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Wernimont, A., Huffman, D., Lamb, A. et al. Structural basis for copper transfer by the metallochaperone for the Menkes/Wilson disease proteins. Nat Struct Mol Biol 7, 766–771 (2000). https://doi.org/10.1038/78999

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