Structural and Biophysical Basis for PFAS Binding by Human Sterol Carrier Protein-2

Abstract

Per- and polyfluoroalkyl substances (PFAS) are harmful environmental contaminants that bioaccumulate in human tissues and are linked to adverse health outcomes. While PFAS are known to bind to a variety lipid binding proteins (LBPs), such as human serum albumin and fatty acid-binding proteins (FABPs), the broader molecular basis for their biological distribution and additional target proteins in humans remains unanswered. Motivated by its known promiscuity towards a range of hydrophobic ligands, we investigated the interaction between human sterol carrier protein 2 (SCP2) and various PFAS. SCP2 is a structurally distinct LBP with no previously reported affinity for PFAS. Using a combination of screening, fluorescence displacement assays, protein structure prediction of PFAS-SCP2 complexes, ITC, and NMR experiments, we demonstrate for the first time that SCP2 is a PFAS-binding protein. Our findings provide insight into the residues participating in these interactions and provide evidence for an additional LBP that may facilitate PFAS distribution and persistence in the human body.