{
  "abstract": "Annexins are Ca² ⁺ - and membrane-binding proteins conserved across eukaryotes and involved in diverse membrane-associated processes, including unconventional protein secretion (UPS). In the intestinal parasite Giardia lamblia, annexins are represented by a family of 21 proteins termed alpha-giardins (αGs), all of which lack classical signal peptides yet are detected at the parasite surface and in the secretome. Here, we present a comprehensive functional analysis of αGs, with a particular focus on α1-giardin (α1G), a leading vaccine candidate against giardiasis and a putative virulence-associated UPS substrate. We show that αGs localize to peripheral endocytic compartments (PECs-PVs), specialized endo-lysosomal organelles implicated in protein release, and engage in multiprotein complexes enriched in UPS substrates. Using lipid-binding assays, cross-linking mass spectrometry (XL-MS), and structural modelling, we define conserved and divergent features of αG membrane interactions. Focusing on α1G, we combine site-directed mutagenesis, confocal microscopy, and mass photometry to demonstrate a critical role for its short N-terminal region in oligomerization and membrane association. Integration of these data with molecular dynamics simulations reveals how α1G oligomeric state and membrane occupancy could be regulated at PECs-PVs membranes. Taken together, our findings provide structural insights relevant to parasite virulence and vaccine development and contribute to a mechanistic model for annexin-mediated UPS in Giardia. Author summary: Annexins are proteins found in many organisms that help cells interact with membranes and transport materials without using standard secretory pathways. In the intestinal parasite Giardia lamblia, annexins exist as a family of 21 proteins called alpha-giardins (αGs), which are important for the parasite’s survival and infection. This study focuses on understanding the functions of αGs, especially alpha1-giardin (α1G), a promising vaccine candidate against giardiasis. We show that αGs associating with specialized endolysosomal compartments at the parasite-host interface can bind membrane lipids, unlike their cytosolic counterparts. Using laboratory experiments and computer simulations, we reveal that the short N-terminal region of α1G controls its ability to form oligomers and associate with membranes. These findings provide key mechanistic insights into how αGs interact with membranes in Giardia and support their role as targets for vaccine development against this widespread intestinal parasite.",
  "abstract_shown": true,
  "affiliations": [
    "Institute of Cell Biology, University of Bern, Bern, Switzerland.",
    "Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland.",
    "Research Unit in Bioinformatics (RUBi), Department of Biochemistry, Microbiology and Bioinformatics, Rhodes University, Makhanda, South Africa.",
    "Proteomics & Mass Spectrometry Core Facility, University of Bern, Bern, Switzerland.",
    "National Institute for Theoretical and Computational Studies (NITheCS), Stellenbosch University, Stellenbosch, South Africa.",
    "Multidisciplinary Center for Infectious Diseases, University of Bern, Bern, Switzerland.",
    "Institute for Infectious Diseases, University of Bern, Bern, Switzerland."
  ],
  "article_type": "Research Article",
  "arxiv": null,
  "author_total": 7,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Dawid Warmus"
    },
    {
      "affs": [
        0
      ],
      "name": "Corina D Wirdnam"
    },
    {
      "affs": [
        0
      ],
      "name": "Erina A Balmer"
    },
    {
      "affs": [
        2
      ],
      "name": "Tendai Muronzi"
    },
    {
      "affs": [
        3
      ],
      "name": "Manfred Heller"
    },
    {
      "affs": [
        2,
        4
      ],
      "name": "Özlem Tastan Bishop"
    },
    {
      "affs": [
        0,
        5,
        6
      ],
      "name": "Carmen Faso",
      "orcid": "0000-0002-1831-9365"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/11fjx1755dwjz.bib",
  "cited_by": 0,
  "doi": "10.1371/journal.ppat.1014407",
  "fulltext_url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014407",
  "id": "11fjx1755dwjz",
  "issns": [
    "1553-7374",
    "1553-7366"
  ],
  "landing_url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014407",
  "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",
      "1312|S100 Proteins and Annexins"
    ]
  ],
  "openalex": "W7221772867",
  "pdf_url": "https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1014407&type=printable",
  "pmcid": "PMC13686171",
  "pmid": "42873650",
  "published": "2026-10-14",
  "publisher": "Public Library of Science",
  "ris": "https://research.draconitic.com/paper/11fjx1755dwjz.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:23Z",
      "native_id": "10.1371/journal.ppat.1014407",
      "source": "plos",
      "url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014407"
    },
    {
      "first_seen": "2026-10-30T12:18:46Z",
      "native_id": "MED:42873650",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42873650"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|S100 Proteins and Annexins",
      "subfield": "molecular-biology"
    }
  ],
  "title": "The N-terminus of alpha-1 giardin, a parasitic annexin orthologue, is essential for oligomerization and lipid-binding activity",
  "title_text": "The N-terminus of alpha-1 giardin, a parasitic annexin orthologue, is essential for oligomerization and lipid-binding activity",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:18:46Z",
  "url": "https://research.draconitic.com/paper/11fjx1755dwjz",
  "venue": "PLOS Pathogens",
  "versions": []
}