Metallochaperones and metal-transporting ATPases: A comparative analysis of sequences and structures

Fabio Arnesano, Lucia Banci, Ivano Bertini*, Simone Ciofi-Baffoni, Elena Molteni, David L. Huffman, Thomas V. O'Halloran

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

220 Scopus citations

Abstract

A comparative structural genomic analysis of a new class of metal-trafficking proteins can provide insights into the intracellular chemistry of reactive cofactors such as copper and zinc. Starting from the sequences of the metallochaperone Atx1 and from the first soluble domain of the copper-transporting ATPase Ccc2, both from yeast, a search on the available genomes was performed using a homology criterion and a metal-binding motif x′-x″-C-x‴-x″″-C. By limiting ourselves to 20% identity with any of the proteins found, several soluble copper-transport proteins were identified, as well as soluble domains of membrane-bound ATPases. Structural models were calculated using high-resolution solution structures as templates, and the models were validated using statistical and energy criteria. Residue conservation and substitution have been interpreted and discussed in terms of structure-function relationship. The potential energy surfaces have been analyzed in terms of protein-protein interactions. We find that metallochaperones and their physiological partner ATPases from several phylogenetic kingdoms recognize one another, via an interplay of electrostatics, hydrogen bonding, and hydrophobic interactions, in a manner that precisely orients the metal-binding side chains for rapid metal transfer between otherwise tight binding sites. Finally, other putative metal-transport proteins are mentioned that have low homology and/or a different metal-binding consensus motif and that appear to use similar structures for recognition and transfer. This analysis highlights the wealth and the complexity of the field.

Original languageEnglish (US)
Pages (from-to)255-271
Number of pages17
JournalGenome research
Volume12
Issue number2
DOIs
StatePublished - 2002

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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