Zinc Binding Controls Protein Interactions

Protein-protein interactions, which are key to nearly all cellular processes, are guided by formation of many weak, noncovalent bonds (such as hydrogen bonds) spread over large molecular surfaces. Inspired by the use of metal ions and small organic ligands to build supramolecular complexes, F. Akif Tezcan, Eric N. Salgado, and Jasmin Faraone-Mennella of the University of California, San Diego, now show that the strength and selectivity of a few metal-ligand bonds alone can control the assembly of multiprotein structures (J. Am. Chem. Soc., DOI: 10.1021/ja075261o). The researchers demonstrated the concept by adding Zn(II) to cytochrome cb₅₆₂, a four-helix bundle heme protein. They first modified the protein to contain pairs of histidine residues on one helix that can bind zinc ions, which subsequently nucleate protein-protein interactions. Altogether, four zinc atoms and four protein molecules self-assemble into 16-helix macromolecules. These aggregates are readily dissolved by adding a metal chelator, such as EDTA, or by lowering the pH below 6. The researchers believe metal-ion control of protein-protein interactions could lead to new biomaterials or manipulation of cellular processes.