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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.<\/jats:p>","DOI":"10.1101\/2025.10.27.684906","type":"posted-content","created":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T20:00:15Z","timestamp":1761681615000},"source":"Crossref","is-referenced-by-count":0,"title":["Structural and Biophysical Basis for PFAS Binding by Human Sterol Carrier Protein-2"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9402-7615","authenticated-orcid":false,"given":"Aaron S.","family":"Birchfield","sequence":"first","affiliation":[{"name":"Department of Chemistry, Virginia Commonwealth University, Richmond, VA 23284, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-7778-269X","authenticated-orcid":false,"given":"Rachel L.","family":"Signorelli","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Virginia Commonwealth University, Richmond, VA 23284, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyla T.","family":"Cang","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Virginia Commonwealth University, Richmond, VA 23284, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4647-903X","authenticated-orcid":false,"given":"C\u00e9sar A.","family":"Ram\u00edrez-Sarmiento","sequence":"additional","affiliation":[{"name":"Institute for Biological and Medical Engineering, Schools of Engineering, Medicine and Biological Sciences, Pontificia Universidad Cat\u00f3lica de Chile, Santiago 7820436, Chile"},{"name":"ANID, Millennium Science Initiative Program, Millennium Institute for Integrative Biology (iBio), Santiago 8331150, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8304-8269","authenticated-orcid":false,"given":"Brian","family":"Fuglestad","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Virginia Commonwealth University, Richmond, VA 23284, U.S.A."},{"name":"The Center for Drug Discovery, Virginia Commonwealth University, Richmond, VA 23298, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026061107450715000_2025.10.27.684906v2.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.envint.2024.108577"},{"key":"2026061107450715000_2025.10.27.684906v2.2","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfae061"},{"key":"2026061107450715000_2025.10.27.684906v2.3","doi-asserted-by":"crossref","first-page":"dvac010","DOI":"10.1093\/eep\/dvac010","article-title":"Nephrotoxicity of perfluorooctane sulfonate (PFOS)\u2014effect on transcription and epigenetic factors","volume":"8","year":"2022","journal-title":"Environ. 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