{
  "abstract": "Lipid-protein interactions play critical roles in cellular function, yet their site-resolved characterization remains challenging due to the dynamic nature of lipid binding and the limited availability of chemoselective strategies for covalently capturing native lipid-protein contacts. Here, we introduce aziridination-based lipid-protein crosslinking coupled with mass spectrometry (Azi-LPXL-MS), a chemoselective strategy that installs an N-H aziridine moiety onto acyl chains of native unsaturated lipids and enables subsequent crosslinking to proximal lysine residues using the amine-reactive reagent disuccinimidyl suberate (DSS). This integrated workflow simultaneously identifies lipid-binding sites and intraprotein peptide-peptide distance constraints, providing direct insight into lipid binding and binding-induced conformational changes within a single experiment. Application of Azi-LPXL-MS to β-lactoglobulin (BLG) demonstrates these capabilities, consistent with known structural models, while additionally providing solution-phase and conformational information not accessible from static structures alone. The power of the method is further demonstrated in the integral membrane enzyme diacylglycerol acyltransferase 1 (DGAT1). Azi-LPXL-MS reveals phosphatidic acid (PA)-binding sites and maps lipid-dependent conformational rearrangements across both resolved and previously uncharacterized regions. These data further define an allosteric conformational network linking lipid engagement to distal structural changes. Integrated with site-directed mutagenesis and molecular docking, two potential PA-binding sites in DGAT1, located in a surface pocket and an internal chamber, were identified and functionally validated, further supporting the experimental findings. These results establish Azi-LPXL-MS as a site-resolved method for studying lipid-protein interactions, providing insight into how individual lipid species engage proteins and influence their conformations in biological systems.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Chemistry, Texas A&M University, 580 Ross Street, College Station, Texas77843, United States.",
    "Department of Biochemistry and Biophysics, Texas A&M University, 300 Olsen Boulevard, College Station, Texas77843, United States."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 10,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Chia-Lung Tsai",
      "orcid": "0009-0008-7901-7142"
    },
    {
      "affs": [
        1
      ],
      "name": "Atiya Tahira Tasnim",
      "orcid": "0000-0001-7802-3948"
    },
    {
      "affs": [
        0
      ],
      "name": "Zhenyu Xi"
    },
    {
      "affs": [
        0
      ],
      "name": "Syuan-Ting Kuo"
    },
    {
      "affs": [
        0
      ],
      "name": "Gopal Reddy Ramidi"
    },
    {
      "affs": [
        0
      ],
      "name": "Jiaxin Feng"
    },
    {
      "affs": [
        0
      ],
      "name": "Michael Ryan Eastabrook"
    },
    {
      "affs": [
        0
      ],
      "name": "David H Russell",
      "orcid": "0000-0003-0830-3914"
    },
    {
      "affs": [
        1
      ],
      "name": "Xuewu Sui"
    },
    {
      "affs": [
        0
      ],
      "name": "Xin Yan",
      "orcid": "0000-0002-8292-130X"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/ax58jasdat8p0.bib",
  "cited_by": 0,
  "doi": "10.1021/jacs.6c08027",
  "fulltext_url": "https://europepmc.org/articles/PMC13693381",
  "id": "ax58jasdat8p0",
  "issns": [
    "0002-7863",
    "1520-5126"
  ],
  "landing_url": "https://europepmc.org/article/MED/42912306",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1607|Mass Spectrometry Techniques and Applications"
    ]
  ],
  "openalex": "W7165965593",
  "pdf_url": "https://europepmc.org/articles/PMC13693381?pdf=render",
  "pmcid": "PMC13693381",
  "pmid": "42912306",
  "published": "2026-10-01",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/ax58jasdat8p0.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:20:14Z",
      "native_id": "MED:42912306",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42912306"
    }
  ],
  "subjects": [
    {
      "field": "chemistry",
      "origin": "openalex:1607|Mass Spectrometry Techniques and Applications",
      "subfield": "physical"
    }
  ],
  "title": "Aziridination-Based Crosslinking Enables Site-Resolved Elucidation of Lipid Binding and Protein Conformational Changes.",
  "title_text": "Aziridination-Based Crosslinking Enables Site-Resolved Elucidation of Lipid Binding and Protein Conformational Changes.",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:20:14Z",
  "url": "https://research.draconitic.com/paper/ax58jasdat8p0",
  "venue": "Journal of the American Chemical Society",
  "versions": []
}