The N-terminus of alpha-1 giardin, a parasitic annexin orthologue, is essential for oligomerization and lipid-binding activity
7 affiliations
- 1Institute of Cell Biology, University of Bern, Bern, Switzerland.
- 2Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland.
- 3Research Unit in Bioinformatics (RUBi), Department of Biochemistry, Microbiology and Bioinformatics, Rhodes University, Makhanda, South Africa.
- 4Proteomics & Mass Spectrometry Core Facility, University of Bern, Bern, Switzerland.
- 5National Institute for Theoretical and Computational Studies (NITheCS), Stellenbosch University, Stellenbosch, South Africa.
- 6Multidisciplinary Center for Infectious Diseases, University of Bern, Bern, Switzerland.
- 7Institute for Infectious Diseases, University of Bern, Bern, Switzerland.
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.
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BibTeX
@article{warmus2026nterminus,
title = {{The N-terminus of alpha-1 giardin, a parasitic annexin orthologue, is essential for oligomerization and lipid-binding activity}},
author = {Dawid Warmus and Corina D Wirdnam and Erina A Balmer and Tendai Muronzi and Manfred Heller and Özlem Tastan Bishop and Carmen Faso},
journal = {PLOS Pathogens},
year = {2026},
month = oct,
doi = {10.1371/journal.ppat.1014407},
url = {https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014407},
note = {CC BY},
}
RIS
TY - JOUR
TI - The N-terminus of alpha-1 giardin, a parasitic annexin orthologue, is essential for oligomerization and lipid-binding activity
AU - Dawid Warmus
AU - Corina D Wirdnam
AU - Erina A Balmer
AU - Tendai Muronzi
AU - Manfred Heller
AU - Özlem Tastan Bishop
AU - Carmen Faso
PY - 2026
DA - 2026/10/14
JO - PLOS Pathogens
DO - 10.1371/journal.ppat.1014407
UR - https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014407
AB - 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.
SN - 1553-7374
SN - 1553-7366
ER -