Cd(II)- and Pb(II)-Induced Self-Assembly of Peripheral Membrane Domains from Protein Kinase C

Cd²⁺ and Pb²⁺ are xenobiotic heavy metal ions that use ionic mimicry to interfere with the cellular function of biomacromolecules. Using a combination of SAXS, electron microscopy, FRET, and solution NMR spectroscopy, we demonstrate that treatment with Cd²⁺ and Pb²⁺ causes self-assembly of protein kinase C regulatory domains that peripherally associate with membranes. The self-assembly process successfully competes with ionic mimicry and is mediated by conserved protein regions that are distinct from the canonical Ca²⁺-binding motifs of protein kinase C. The ability of protein oligomers to interact with anionic membranes is enhanced compared to the monomeric species. Our findings suggest that metal-ion-dependent peripheral membrane domains can be utilized for generating protein-metal-ion nanoclusters and serve as biotemplates for the design of sequestration agents.