Conditional Binding of Arsenic Trioxide (ATO) to Cysteine-Rich Zinc Finger Motifs within RBCC Domain of PML Protein

The arsenic trioxide (ATO)-based cure of acute promyelocytic leukemia is attributed to PML/RARα oncoprotein degradation through binding of its RBCC domain (i.e., consist of RING, B-box1, B-box2, and Coiled-coil) with arsenic. Despite ATO being proven to interact with the Cysteine213 triad in the B-box2 trimer of PML-Nuclear Bodies, whether its direct binding to cysteine-rich zinc finger motifs in PML protein, remains unclear. Consequently, we purified the RING, B-box1, and B-box2 domains to assess their potential for arsenic-binding. The results showed that ATO cannot displace zinc ions under physiological conditions but binds with zinc finger domains under zinc-depletion in low-pH conditions, revealing a conditional binding mechanism.