Broad PFAS binding with fatty acid binding protein 4 is enabled by variable binding modes.

Area of Science:

• Environmental Chemistry
• Structural Biology
• Toxicology

Background:

• Per- and polyfluoroalkyl substances (PFAS) are widespread environmental pollutants known to bioaccumulate.
• The molecular mechanisms underlying PFAS interactions with biological proteins are not well understood.
• Human adipocyte fatty acid-binding protein (FABP4) plays a role in metabolic regulation and endocrine function.

Purpose of the Study:

• To investigate the binding interactions between FABP4 and a diverse range of PFAS.
• To elucidate the structural basis of PFAS-FABP4 complex formation.
• To understand how PFAS binding to FABP4 may influence metabolic processes and disease risk.

Main Methods:

• Fluorescence competition assays to measure binding affinities.
• X-ray crystallography to determine the structures of FABP4 in complex with specific PFAS (PFOA, PFDA, PFHxDA).
• Analysis of binding modes and their correlation with chemical properties.

Main Results:

• FABP4 binds a variety of PFAS, including newer replacements and longer-chain compounds.
• Shorter-chain PFAS exhibit measurable binding affinities to FABP4, exceeding those of nonfluorinated analogs.
• Crystal structures reveal three distinct binding modes for PFOA, PFDA, and PFHxDA, with PFOA binding in two sites.
• Binding modes involve enhanced hydrophobic interactions and distinct protein conformations, explaining observed affinities.

Conclusions:

• PFAS-FABP4 interactions are influenced by PFAS chain length, headgroup, and protein conformation.
• PFAS binding to FABP4, even at low affinities, could perturb metabolic regulation due to FABP4's role in endocrine function.
• Structural and biochemical insights are crucial for understanding PFAS transport and toxicological effects.