The X-linked Inhibitor of Apoptosis Protein (XIAP) contains multiple zinc-binding domains to maintain proper structure and function. Putative implication of XIAP in copper homeostasis, coupled with the similar coordination characteristics of copper and zinc in biomolecules, has prompted us to investigate the interaction of copper with the zinc binding domains of XIAP. Herein, we report spectroscopic studies that demonstrate that the RING domain of XIAP binds multiple Cu(I) ions and results in Zn(II) ejection from the protein structure. Moreover, the dimeric structure of the RING domain, which is a strict requirement for its ubiquitin ligase activity, is lost upon copper substitution at the di-zinc binding site. These results will be discussed in the context of metal ion toxicity and metal-modulated protein function.

Cu(I) interactions with zinc finger proteins: Disruption of the di-nuclear zinc binding site in the RING domain of XIAP

ACS Spring 2022

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