Profiling protein targets of cellular toxicant exposure

Environmental agents of exposure can damage proteins, affecting protein function and cellular protein homeostasis. Specific residues are inherently chemically susceptible to damage from individual types of exposure. Amino acid content is not completely predictive of protein susceptibility, as secondary, tertiary, and quaternary structures of proteins strongly influence the reactivity of the proteome to individual exposures. Because we cannot readily predict which proteins will be affected by which chemical exposures, mass spectrometry-based proteomic strategies are necessary to determine the protein targets of environmental toxins and toxicants. This review describes the mechanisms by which environmental exposure to toxins and toxicants can damage proteins and affect their function, and emerging omic methodologies that can be used to identify the protein targets of a given agent. These methods include target identification strategies that have recently revolutionized the drug discovery field, such as activity-based protein profiling, protein footprinting, and protein stability profiling technologies. In particular, we highlight the necessity of multiple, complementary approaches to fully interrogate how protein integrity is challenged by individual exposures.