{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T16:52:23Z","timestamp":1791996743449,"version":"4.4.0"},"reference-count":84,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T00:00:00Z","timestamp":1791936000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001711","name":"Schweizerischer Nationalfonds zur F\u00f6rderung der Wissenschaftlichen Forschung","doi-asserted-by":"publisher","award":["PR00P3_179813"],"award-info":[{"award-number":["PR00P3_179813"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001711","name":"Schweizerischer Nationalfonds zur F\u00f6rderung der Wissenschaftlichen Forschung","doi-asserted-by":"publisher","award":["310030_219372"],"award-info":[{"award-number":["310030_219372"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]},{"name":"GHA-SciEx"},{"name":"Swiss Society for Tropical Medicine and Parasitology"},{"name":"Graduate School for Cellular and Biomedical Sciences, University of Bern","id":[{"id":"https:\/\/ror.org\/02k7v4d05","id-type":"ROR","asserted-by":"crossref"}]},{"name":"National Research Foundation (NRF), South Africa","award":["PSTD2204072582"],"award-info":[{"award-number":["PSTD2204072582"]}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>\n                    Annexins are Ca\u00b2\u2009\u207a\u2009- and membrane-binding proteins conserved across eukaryotes and involved in diverse membrane-associated processes, including unconventional protein secretion (UPS). In the intestinal parasite\n                    <jats:italic>Giardia lamblia<\/jats:italic>\n                    , annexins are represented by a family of 21 proteins termed alpha-giardins (\u03b1Gs), 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 \u03b1Gs, with a particular focus on \u03b11-giardin (\u03b11G), a leading vaccine candidate against giardiasis and a putative virulence-associated UPS substrate. We show that \u03b1Gs 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 \u03b1G membrane interactions. Focusing on \u03b11G, 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 \u03b11G 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.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1014407","type":"journal-article","created":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T16:40:10Z","timestamp":1791996010000},"page":"e1014407","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["The N-terminus of alpha-1 giardin, a parasitic annexin orthologue, is essential for oligomerization and lipid-binding activity"],"prefix":"10.1371","volume":"22","author":[{"given":"Dawid","family":"Warmus","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corina D.","family":"Wirdnam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erina A.","family":"Balmer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tendai","family":"Muronzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manfred","family":"Heller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00d6zlem Tastan","family":"Bishop","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1831-9365","authenticated-orcid":true,"given":"Carmen","family":"Faso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,10,14]]},"reference":[{"key":"ppat.1014407.ref001","article-title":"Annexins: From Structure to Function","author":"V Gerke","year":"2002","journal-title":"Physiological Reviews"},{"issue":"13","key":"ppat.1014407.ref002","doi-asserted-by":"crossref","first-page":"6517","DOI":"10.3390\/ijms26136517","article-title":"Annexin-Membrane Interactions Across Eukaryotic Domains of Life-A Comparative Approach","volume":"26","author":"D Warmus","year":"2025","journal-title":"Int J Mol Sci"},{"issue":"1","key":"ppat.1014407.ref003","doi-asserted-by":"crossref","first-page":"1574","DOI":"10.1038\/s41467-024-45954-0","article-title":"Annexins-a family of proteins with distinctive tastes for cell signaling and membrane dynamics","volume":"15","author":"V Gerke","year":"2024","journal-title":"Nat Commun"},{"issue":"4","key":"ppat.1014407.ref004","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1186\/gb-2004-5-4-219","article-title":"The annexins","volume":"5","author":"SE Moss","year":"2004","journal-title":"Genome Biol"},{"key":"ppat.1014407.ref005","doi-asserted-by":"crossref","unstructured":"Liemann S, Lewit-Bentley A. Annexins: a novel family of calcium-and membrane-binding proteins in search of a function. 1995.","DOI":"10.1016\/S0969-2126(01)00152-6"},{"key":"ppat.1014407.ref006","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1016\/S0167-4889(00)00094-X","article-title":"Modes of annexin-membrane interactions analyzed by employing chimeric annexin proteins","volume":"1498","author":"J K\u00f6nig","year":"2000","journal-title":"Biochim Biophys Acta"},{"key":"ppat.1014407.ref007","doi-asserted-by":"crossref","first-page":"2631","DOI":"10.1242\/jcs.01245","article-title":"Annexins--unique membrane binding proteins with diverse functions","volume":"117","author":"U Rescher","year":"2004","journal-title":"J Cell Sci"},{"issue":"4","key":"ppat.1014407.ref008","doi-asserted-by":"crossref","first-page":"2437","DOI":"10.1074\/jbc.M210286200","article-title":"Interfacial basic cluster in annexin V couples phospholipid binding and trimer formation on membrane surfaces","volume":"278","author":"Y Mo","year":"2003","journal-title":"J Biol Chem"},{"key":"ppat.1014407.ref009","article-title":"Annexin A2 facilitates endocytic trafficking of antisense oligonucleotides","volume":"44","author":"S Wang","year":"2016","journal-title":"Nucleic Acids Research"},{"issue":"7","key":"ppat.1014407.ref010","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0040429","article-title":"Annexin A1 and A2: roles in retrograde trafficking of Shiga toxin","volume":"7","author":"L Tcatchoff","year":"2012","journal-title":"PLoS One"},{"issue":"11","key":"ppat.1014407.ref011","doi-asserted-by":"crossref","first-page":"3015","DOI":"10.1021\/bi9922401","article-title":"Annexins V and XII insert into bilayers at mildly acidic pH and form ion channels","volume":"39","author":"JM Isas","year":"2000","journal-title":"Biochemistry"},{"issue":"5132","key":"ppat.1014407.ref012","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1126\/science.7692599","article-title":"Structure-function analysis of the ion channel selectivity filter in human annexin V","volume":"262","author":"R Berendes","year":"1993","journal-title":"Science"},{"key":"ppat.1014407.ref013","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/0014-5793(90)81428-Q","article-title":"The calcium binding sites in human annexin V by crystal structure analysis at 2.0 A resolution. Implications for membrane binding and calcium channel activity","volume":"275","author":"R Huber","year":"1990","journal-title":"FEBS Lett"},{"issue":"6","key":"ppat.1014407.ref014","first-page":"1083","article-title":"Acidic pH-induced folding of annexin VI is a prerequisite for its insertion into lipid bilayers and formation of ion channels by the protein molecules","volume":"15","author":"M Golczak","year":"2001","journal-title":"FASEB J"},{"issue":"10","key":"ppat.1014407.ref015","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1515\/hsz-2016-0171","article-title":"Annexins in plasma membrane repair","volume":"397","author":"TL Boye","year":"2016","journal-title":"Biol Chem"},{"issue":"46","key":"ppat.1014407.ref016","doi-asserted-by":"crossref","first-page":"35202","DOI":"10.1074\/jbc.M606406200","article-title":"Requirement for annexin A1 in plasma membrane repair","volume":"281","author":"AK McNeil","year":"2006","journal-title":"J Biol Chem"},{"issue":"1","key":"ppat.1014407.ref017","doi-asserted-by":"crossref","first-page":"6726","DOI":"10.1038\/s41598-019-43143-4","article-title":"Annexin A7 is required for ESCRT III-mediated plasma membrane repair","volume":"9","author":"SL S\u00f8nder","year":"2019","journal-title":"Sci Rep"},{"key":"ppat.1014407.ref018","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1038\/ncomms1270","article-title":"Annexin-A5 assembled into two-dimensional arrays promotes cell membrane repair","volume":"2","author":"A Bouter","year":"2011","journal-title":"Nat Commun"},{"issue":"1","key":"ppat.1014407.ref019","doi-asserted-by":"crossref","first-page":"2174288","DOI":"10.1080\/21505594.2023.2174288","article-title":"A core UPS molecular complement implicates unique endocytic compartments at the parasite-host interface in Giardia lamblia","volume":"14","author":"EA Balmer","year":"2023","journal-title":"Virulence"},{"key":"ppat.1014407.ref020","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.semcdb.2018.02.022","article-title":"Unconventional secretion of annexins and galectins","volume":"83","author":"SJ Popa","year":"2018","journal-title":"Semin Cell Dev Biol"},{"issue":"11","key":"ppat.1014407.ref021","doi-asserted-by":"crossref","first-page":"2477","DOI":"10.3390\/cells9112477","article-title":"Special Issue \u201cRecent Developments in Annexin Biology\u201d","volume":"9","author":"U Rescher","year":"2020","journal-title":"Cells"},{"issue":"44","key":"ppat.1014407.ref022","doi-asserted-by":"crossref","first-page":"13469","DOI":"10.1021\/bi001275u","article-title":"Mechanism of annexin I-mediated membrane aggregation","volume":"39","author":"E Bitto","year":"2000","journal-title":"Biochemistry"},{"issue":"1","key":"ppat.1014407.ref023","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1006\/jsbi.2000.4337","article-title":"Trimers, dimers of trimers, and trimers of trimers are common building blocks of annexin a5 two-dimensional crystals","volume":"133","author":"F Oling","year":"2001","journal-title":"J Struct Biol"},{"issue":"2","key":"ppat.1014407.ref024","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1016\/j.bbamem.2007.11.004","article-title":"Insight into the location and dynamics of the annexin A2 N-terminal domain during Ca(2+)-induced membrane bridging","volume":"1778","author":"J Ayala-Sanmartin","year":"2008","journal-title":"Biochim Biophys Acta"},{"issue":"1","key":"ppat.1014407.ref025","doi-asserted-by":"crossref","first-page":"14662","DOI":"10.1038\/s41598-018-33044-3","article-title":"Bridging of membrane surfaces by annexin A2","volume":"8","author":"D Grill","year":"2018","journal-title":"Sci Rep"},{"issue":"24","key":"ppat.1014407.ref026","doi-asserted-by":"crossref","first-page":"14060","DOI":"10.1073\/pnas.95.24.14060","article-title":"A transmembrane form of annexin XII detected by site-directed spin labeling","volume":"95","author":"R Langen","year":"1998","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ppat.1014407.ref027","doi-asserted-by":"crossref","first-page":"3402","DOI":"10.1021\/bi047805u","article-title":"Reversible transition between the surface trimer and membrane-inserted monomer of annexin 12","volume":"44","author":"AS Ladokhin","year":"2005","journal-title":"Biochemistry"},{"issue":"3","key":"ppat.1014407.ref028","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1093\/jxb\/erm344","article-title":"Annexins: multifunctional components of growth and adaptation","volume":"59","author":"JC Mortimer","year":"2008","journal-title":"J Exp Bot"},{"issue":"1","key":"ppat.1014407.ref029","first-page":"147","article-title":"Functional identification of alpha 1-giardin as an annexin of Giardia lamblia","volume":"173","author":"B Bauer","year":"1999","journal-title":"FEMS Microbiol Lett"},{"issue":"1","key":"ppat.1014407.ref030","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/S0020-7519(02)00228-X","article-title":"The cytoskeleton of Giardia lamblia","volume":"33","author":"HG Elmendorf","year":"2003","journal-title":"Int J Parasitol"},{"issue":"28","key":"ppat.1014407.ref031","doi-asserted-by":"crossref","first-page":"25703","DOI":"10.1074\/jbc.M203260200","article-title":"Annexin XXI (ANX21) of Giardia lamblia has sequence motifs uniquely sdhared by giardial annexins and is specifically localized in the flagella","volume":"277","author":"A Szkodowska","year":"2002","journal-title":"J Biol Chem"},{"issue":"2","key":"ppat.1014407.ref032","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1007\/s00436-007-0758-6","article-title":"alpha14-Giardin (annexin E1) is associated with tubulin in trophozoites of Giardia lamblia and forms local slubs in the flagella","volume":"102","author":"A Vahrmann","year":"2008","journal-title":"Parasitol Res"},{"issue":"4","key":"ppat.1014407.ref033","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1016\/j.exppara.2010.05.028","article-title":"Giardia lamblia: intracellular localization of alpha8-giardin","volume":"126","author":"CJ Wei","year":"2010","journal-title":"Exp Parasitol"},{"issue":"12","key":"ppat.1014407.ref034","doi-asserted-by":"crossref","first-page":"1341","DOI":"10.1016\/S0020-7519(03)00201-7","article-title":"Characterisation of alpha-1 giardin: an immunodominant Giardia lamblia annexin with glycosaminoglycan-binding activity","volume":"33","author":"ME-L Weiland","year":"2003","journal-title":"Int J Parasitol"},{"issue":"2","key":"ppat.1014407.ref035","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.jmb.2012.06.041","article-title":"Alpha-1 giardin is an annexin with highly unusual calcium-regulated mechanisms","volume":"423","author":"SK Weeratunga","year":"2012","journal-title":"J Mol Biol"},{"key":"ppat.1014407.ref036","doi-asserted-by":"crossref","DOI":"10.1128\/mSphere.00032-15","article-title":"Comparative Cell Biology and Evolution of Annexins in Diplomonads","volume":"1","author":"E Einarsson","year":"2016","journal-title":"mSphere"},{"issue":"6","key":"ppat.1014407.ref037","doi-asserted-by":"crossref","DOI":"10.1128\/IAI.00219-19","article-title":"Identification of Conserved Candidate Vaccine Antigens in the Surface Proteome of Giardia lamblia","volume":"87","author":"BJ Davids","year":"2019","journal-title":"Infect Immun"},{"issue":"3","key":"ppat.1014407.ref038","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1093\/gigascience\/giy003","article-title":"Giardia secretome highlights secreted tenascins as a key component of pathogenesis","volume":"7","author":"A Dubourg","year":"2018","journal-title":"Gigascience"},{"issue":"12","key":"ppat.1014407.ref039","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pntd.0006120","article-title":"Characterization of the Giardia intestinalis secretome during interaction with human intestinal epithelial cells: The impact on host cells","volume":"11","author":"SY Ma\u2019ayeh","year":"2017","journal-title":"PLoS Negl Trop Dis"},{"issue":"2","key":"ppat.1014407.ref040","doi-asserted-by":"crossref","DOI":"10.1371\/journal.ppat.1008317","article-title":"Phosphoinositide-binding proteins mark, shape and functionally modulate highly-diverged endocytic compartments in the parasitic protist Giardia lamblia","volume":"16","author":"L Cernikova","year":"2020","journal-title":"PLoS Pathog"},{"issue":"9","key":"ppat.1014407.ref041","doi-asserted-by":"crossref","DOI":"10.1371\/journal.ppat.1007250","article-title":"Five facts about Giardia lamblia","volume":"14","author":"L Cernikova","year":"2018","journal-title":"PLoS Pathog"},{"issue":"1","key":"ppat.1014407.ref042","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1186\/s12915-022-01402-3","article-title":"Combined nanometric and phylogenetic analysis of unique endocytic compartments in Giardia lamblia sheds light on the evolution of endocytosis in Metamonada","volume":"20","author":"R Santos","year":"2022","journal-title":"BMC Biol"},{"key":"ppat.1014407.ref043","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/bs.apar.2019.08.001","article-title":"A cytonaut\u2019s guide to protein trafficking in Giardia lamblia","volume":"106","author":"C Faso","year":"2019","journal-title":"Adv Parasitol"},{"issue":"12","key":"ppat.1014407.ref044","doi-asserted-by":"crossref","first-page":"1600","DOI":"10.3390\/cells8121600","article-title":"Exosome Biogenesis in the Protozoa Parasite Giardia lamblia: A Model of Reduced Interorganellar Crosstalk","volume":"8","author":"S Moyano","year":"2019","journal-title":"Cells"},{"issue":"3","key":"ppat.1014407.ref045","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1016\/j.jsb.2019.07.002","article-title":"The peripheral vesicles gather multivesicular bodies with different behavior during the Giardia intestinalis life cycle","volume":"207","author":"V Midlej","year":"2019","journal-title":"J Struct Biol"},{"issue":"8","key":"ppat.1014407.ref046","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1111\/pim.12210","article-title":"Host defences against Giardia lamblia","volume":"37","author":"G Lopez-Romero","year":"2015","journal-title":"Parasite 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Protoc"},{"issue":"4","key":"ppat.1014407.ref050","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1093\/mp\/sst171","article-title":"Annexin5 is essential for pollen development in Arabidopsis","volume":"7","author":"J Zhu","year":"2014","journal-title":"Mol Plant"},{"issue":"8","key":"ppat.1014407.ref051","doi-asserted-by":"crossref","first-page":"2833","DOI":"10.1021\/bi047642+","article-title":"The conserved core domains of annexins A1, A2, A5, and B12 can be divided into two groups with different Ca2+-dependent membrane-binding properties","volume":"44","author":"DR Patel","year":"2005","journal-title":"Biochemistry"},{"issue":"6","key":"ppat.1014407.ref052","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1080\/07391102.1993.10508696","article-title":"Structure-function correlations of calcium binding and calcium channel activities based on 3-dimensional models of human annexins I, II, III, V and VII","volume":"10","author":"JM Chen","year":"1993","journal-title":"J Biomol Struct Dyn"},{"issue":"7","key":"ppat.1014407.ref053","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1016\/0968-0004(94)90002-7","article-title":"Annexin V: the key to understanding ion selectivity and voltage regulation?","volume":"19","author":"P Demange","year":"1994","journal-title":"Trends Biochem Sci"},{"issue":"1","key":"ppat.1014407.ref054","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1093\/jxb\/erab419","article-title":"Arabidopsis annexin 5 is involved in maintenance of pollen membrane integrity and permeability","volume":"73","author":"M Lichocka","year":"2022","journal-title":"J Exp Bot"},{"key":"ppat.1014407.ref055","doi-asserted-by":"crossref","DOI":"10.1016\/S0188-0128(99)00040-8","article-title":"Mutation of Highly Conserved Arginine Residues Disrupts the Structure and Function of Annexin V","volume":"30","author":"B Campos","year":"1999","journal-title":"Archives of Medical 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Abramson","year":"2024","journal-title":"Nature"},{"issue":"4","key":"ppat.1014407.ref065","doi-asserted-by":"crossref","first-page":"720","DOI":"10.1016\/j.jmb.2015.09.014","article-title":"The HADDOCK2.2 Web Server: User-Friendly Integrative Modeling of Biomolecular Complexes","volume":"428","author":"GCP van Zundert","year":"2016","journal-title":"J Mol Biol"},{"issue":"7","key":"ppat.1014407.ref066","doi-asserted-by":"crossref","first-page":"1731","DOI":"10.1021\/ja026939x","article-title":"HADDOCK: a protein-protein docking approach based on biochemical or biophysical information","volume":"125","author":"C Dominguez","year":"2003","journal-title":"J Am Chem Soc"},{"issue":"1","key":"ppat.1014407.ref067","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1002\/pro.3943","article-title":"UCSF ChimeraX: Structure visualization for researchers, educators, and developers","volume":"30","author":"EF Pettersen","year":"2021","journal-title":"Protein 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