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Updated: Jun 7, 2026
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Mapping Dysfunctional Protein-Protein Interactions in Disease
Published on: October 24, 2025
High-throughput protein target mapping enables accelerated bioactivity discovery for ToxCast and PFAS compounds
Diwen Yang1, Xiaoyun Wang2, Jiabao Liu2,3
1Department of Physical and Environmental Sciences, University of Toronto Scarborough, Toronto, ON M1C 1A4, Canada.
Summary
This study used ultrahigh-throughput screening to identify protein targets for chemical pollutants. Fatty acid-binding proteins (FABPs) were found to bind per- and polyfluoroalkyl substances (PFAS), with implications for understanding chemical toxicity.
Area of Science:
- Environmental Chemistry
- Biochemistry
- Toxicology
Background:
- Chemical pollution poses a global health risk, but contaminant toxicity mechanisms are largely unknown.
- Identifying protein targets is crucial for understanding chemical toxicity and risk assessment.
Purpose of the Study:
- To systematically identify protein targets of prioritized chemical contaminants using an ultrahigh-throughput affinity selection-mass spectrometry (AS-MS) platform.
- To investigate the binding patterns of per- and polyfluoroalkyl substances (PFAS) to fatty acid-binding proteins (FABPs).
Main Methods:
- Benchmarking and application of an ultrahigh-throughput AS-MS platform.
- Screening of 481 chemicals against 50 human proteins, including ToxCast chemicals and PFAS.
- Validation of identified interactions using X-ray crystallography.
Main Results:
- Discovered 35 interactions between 13 proteins and 481 chemicals.
- Fatty acid-binding proteins (FABPs) were identified as the most ligandable protein family.
- Distinct PFAS binding patterns observed: legacy PFAS bound to FABP1, while alternative PFAS interacted with all FABPs, facilitated by enhanced molecular flexibility.
Conclusions:
- AS-MS is a powerful platform for discovering protein targets beyond existing databases like ToxCast.
- Alternative PFAS exhibit a broader protein-binding spectrum than anticipated, raising concerns about their potential as regrettable substitutes.
- Understanding these interactions is vital for assessing the health risks associated with chemical pollution.
