title: Differential binding of monomethylarsonous acid compared to arsenite and arsenic trioxide with zinc finger peptides and proteins.
abstract: 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.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center , Albuquerque, New Mexico 87131, United States.
authors.forename: Xixi
authors.initials: X
authors.lastname: Zhou
authors.forename: Xi
authors.initials: X
authors.lastname: Sun
authors.forename: Charlotte
authors.initials: C
authors.lastname: Mobarak
authors.forename: A Jay
authors.initials: AJ
authors.lastname: Gandolfi
authors.forename: Scott W
authors.initials: SW
authors.lastname: Burchiel
authors.forename: Laurie G
authors.initials: LG
authors.lastname: Hudson
authors.forename: Ke Jian
authors.initials: KJ
authors.lastname: Liu
mesh_terms: D000595:Amino Acid Sequence; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000737:chemistry*; D018053:Arsenites / Q000737:chemistry*; D002460:Cell Line; D006801:Humans; D013058:Mass Spectrometry; D008969:Molecular Sequence Data; D009942:Organometallic Compounds / Q000737:chemistry*; D010087:Oxides / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry*; D011506:Proteins / Q000737:chemistry*; D013050:Spectrometry, Fluorescence; D013056:Spectrophotometry, Ultraviolet; D016335:Zinc Fingers
chemical_list: D001152:Arsenicals; D018053:Arsenites; D009942:Organometallic Compounds; D010087:Oxides; D010455:Peptides; D011506:Proteins; C406082:monomethylarsonous acid; C015001:arsenite; D000077237:Arsenic Trioxide