High-throughput protein target mapping enables accelerated bioactivity discovery for ToxCast and PFAS compounds
Yang, D.; Wang, X.; Liu, J.; Nair, P.; Sun, J.; Gong, Y.; Qian, X.; Cui, C.; Zeng, H.; Dong, A.; Harding, R. J.; Burgess-Brown, N.; Beyett, T. S.; Song, D.; Krause, H.; Diamond, M. L.; Bolhuis, D. L.; Brown, N. G.; Arrowsmith, C. H.; Edwards, A. M.; Halabelian, L.; Peng, H.
Show abstract
Chemical pollution is a global threat to human health, yet the toxicity mechanism of most contaminants remains unknown. Here, we applied an ultrahigh-throughput affinity-selection mass spectrometry (AS-MS) platform to systematically identify protein targets of prioritized chemical contaminants. After benchmarking the platform, we screened 50 human proteins against 481 prioritized chemicals, including 446 ToxCast chemicals and 35 per-and polyfluoroalkyl substances (PFAS). Among 24,050 interactions assessed, we discovered 35 novel interactions involving 14 proteins, with fatty acid-binding proteins (FABPs) emerging as the most ligandable protein family. Given this, we selected FABPs for further validation, which revealed a distinct PFAS binding pattern: legacy PFAS selectively bound to FABP1, whereas replacement compounds, PFECAs, unexpectedly interacted with all FABPs. X-ray crystallography further revealed that the ether group enhances molecular flexibility of alternative PFAS, to accommodate the binding pockets of FABPs. Our findings demonstrate that AS-MS is a robust platform for the discovery of novel protein targets beyond the scope of the ToxCast program and highlight the broader protein-binding spectrum of alternative PFAS as potential regrettable substitutes.
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