Arsenic is an environmental toxin that enhances the carcinogenic effect of
DNA-damaging agents, such as ultraviolet radiation and
benzo[a]pyrene. Interaction with zinc finger
proteins has been shown to be an important molecular mechanism for
arsenic toxicity and
cocarcinogenesis.
Arsenicals such as
arsenite,
arsenic trioxide (ATO), and
monomethylarsonous acid (
MMA(III)) have been reported to interact with
cysteine residues of zinc finger domains, but little is known about potential differences in their selectivity of interaction. Herein we analyzed the interaction of
arsenite,
MMA(III), and ATO with C2H2, C3H1, and C4 configurations of zinc fingers using UV-vis,
cobalt, fluorescence, and mass spectrometry. We observed that
arsenite and ATO both selectively bound to C3H1 and C4 zinc fingers, while
MMA(III) interacted with all three configurations of zinc finger
peptides. Structurally and functionally,
arsenite and ATO caused conformational changes and
zinc loss on C3H1 and C4 zinc finger
peptide and
protein, respectively, whereas
MMA(III) changed conformation and displaced
zinc on all three types of zinc fingers. The differential selectivity was also demonstrated in zinc finger
proteins isolated from cells treated with these
arsenicals. Our results show that trivalent inorganic
arsenic compounds,
arsenite and ATO, have the same selectivity and behavior when interacting with zinc finger
proteins, while methylation removes the selectivity. These findings provide insights on the molecular mechanisms underlying the differential effects of inorganic versus methylated
arsenicals, as well as the role of in vivo
arsenic methylation in
arsenic toxicity and
carcinogenesis.