The structure of HiSiaQM defines the architecture of tripartite ATP-independent periplasmic (TRAP) transporters
Open accessPreprint — published as 10.1038/s41467-022-31907-y · Paper page
Abstract
Summary: Tripartite ATP-independent periplasmic (TRAP) transporters are widespread in bacteria and archaea and provide important uptake routes for many metabolites 1–3 . They consist of three structural domains, a soluble substrate-binding protein (P-domain), and two transmembrane domains (Q- and M-domains) that form a functional unit 4 . While the structures of the P-domains are well-known, an experimental structure of any QM-domain has been elusive. HiSiaPQM is a TRAP transporter for the monocarboxylate sialic acid, which plays a key role in the virulence of pathogenic bacteria 5 . Here, we present the first cryo-electron microscopy structure of the membrane domains of HiSiaPQM reconstituted in lipid nanodiscs. The reconstruction reveals that TRAP transporters consist of 15 transmembrane helices and are structurally related to elevator-type transporters, such as GltPh and VcINDY 6, 7 . Whereas the latter proteins function as multimers, the idiosyncratic Q-domain of TRAP transporters enables the formation of a monomeric elevator architecture. Structural and mutational analyses together with an AlphaFold 8 model of the tripartite (PQM) complex reveal the structural and conformational coupling of the substrate-binding protein to the transporter domains. Furthermore, we characterize high-affinity VHHs that bind to the periplasmic side of HiSiaQM and inhibit sialic acid uptake in vivo . Thereby, they also confirm the orientation of the protein in the membrane. Our study provides the first structure of any binding-protein dependent secondary transporter and provides starting points for the development of specific inhibitors.
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Mulligan, C., & Mindell, J. A. (2017) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/bs.mie.2017.05.012 · Cited by 10 · see citing works
The archaeal glutamate transporter homologue GltPh shows heterogeneous substrate binding
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Ren, F., Ding, X., Zheng, M., Korzinkin, M., Cai, X., Zhu, W., Mantsyzov, A., Aliper, A., Aladinskiy, V., Cao, Z., et al. (2023) · Chemical Science · doi:10.1039/d2sc05709c · Cited by 365 · see citing works
Ion and lipid orchestration of secondary active transport
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Self-citationLipid packing is disrupted in copolymeric nanodiscs compared with intact membranes
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The ultra-high affinity transport proteins of ubiquitous marine bacteria
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Structure and mechanism of a tripartite ATP-independent periplasmic TRAP transporter
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Currie, M. J., Davies, J. S., Scalise, M., Gulati, A., Wright, J. D., Newton-Vesty, M. C., Abeysekera, G. S., Subramanian, R., Wahlgren, W. Y., Friemann, R., et al. (2024) · eLife · doi:10.7554/elife.92307 · Cited by 20 · see citing works
Peter, M. F., Ruland, J. A., Kim, Y., Hendricks, P., Schneberger, N., Siebrasse, J. P., Thomas, G. H., Kubitscheck, U., & Hagelueken, G. (2024) · Nature Communications · doi:10.1038/s41467-023-44327-3 · Cited by 17 · see citing works
Self-citationInfection of human organoids supports an intestinal niche for Chlamydia trachomatis
Hovhannisyan, P., Stelzner, K., Keicher, M., Paprotka, K., Neyazi, M., Paužuolis, M., Ali, W. M., Rajeeve, K., Bartfeld, S., & Rudel, T. (2024) · PLoS Pathogens · doi:10.1371/journal.ppat.1012144 · Cited by 15 · see citing works
Nanodiscs remain indispensable for Cryo-EM studies of membrane proteins
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TRAPs: the ‘elevator-with-an-operator’ mechanism
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King-Hudson, T.-R., Davies, J. S., Quan, S., Currie, M. J., Tillett, Z. D., Copping, J. M., Panjikar, S., Friemann, R., Allison, J. R., North, R. A., et al. (2024) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2024.107851 · Cited by 8 · see citing works
Membrane-anchored substrate binding proteins are deployed in secondary TAXI transporters
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Structures and Mechanisms of a Novel Bacterial Transport System for Fatty Acids
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Cryo-EM Map Anisotropy Can Be Attenuated by Map Post-Processing and a New Method for Its Estimation
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Structure and selectivity of a glutamate-specific TAXI TRAP binding protein from Vibrio cholerae
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Structural basis of isethionate transport by a TRAP transporter from a sulfate-reducing bacterium
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Combining positive and negative regulation for modular and robust biomolecular control architecturesPreprint
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Characterisation of anhydro-sialic acid transporters from mucosa-associated bacteria
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Jaques, L. M., Davies, J. F. S., Sheldon-Towler, J. J., Kelly, D. J., Leone, V., & Mulligan, C. (2025) · Communications Biology · doi:10.1038/s42003-025-08591-x · Cited by 1 · see citing works
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Jaques, L. M., Davies, J. F. S., Leone, V., Kelly, D. J., & Mulligan, C. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.11.27.625746
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Quan, S., Davies, J. S., North, R. A., Hall, K. R., Turk, L. S., Newton-Vesty, M. C., Dobson, R. C. J., & Allison, J. R. (2026) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.6c01356
- Authors
- Peter, M. F., Depping, P., Schneberger, N., Severi, E., Gatterdam, K., Tindall, S., Durand, A., Heinz, V., Koenig, P.-A., Geyer, M., Ziegler, C., Thomas, G. H., & Hagelueken, G.
- Affiliations
- University of Bonn (DE)
- University of York (GB)
- Institut de génétique et de biologie moléculaire et cellulaire (FR)
- University of Regensburg (DE)
- Corresponding author
- Hagelueken, Gregor
- ORCID
- Venue
- Nature Communications
- Publisher
- openRxiv
- Published
- 2021-12-03
- Volume
- 13
- Issue
- 1
- Pages
- 4471-4471
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC9352664
- OpenAlex
- W4289841189
- Cited by
- 38
- References
- 94
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 18 · 2023: 11 · 2022: 1
- FWCI
- 3.77
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Nature Communications (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion, other-oa)
- Aston Publications Explorer (Aston University) (acceptedVersion, other-oa)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- University of Regensburg Publication Server (University of Regensburg) (submittedVersion)
- Funders
- UK Research and Innovation
- University of Warwick
- Deutsche Forschungsgemeinschaft (HA 6805/4-1, EXC2151390873048, EXC 2151, TRR261, HA6805/5-1, 398967434, 390873048)
- Universität Regensburg
- Rheinische Friedrich-Wilhelms-Universität Bonn (EXC2151-390873048)
- Julius-Maximilians-Universität Würzburg
- Biotechnology and Biological Sciences Research Council (BB/F014759/1)
- Institute of Genetics
- Topics
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Advanced Electron Microscopy Techniques and Applications
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Keywords
- TRAP transporter, substrate-binding protein, transporter structure, nanobodies, lipid nanodiscs
- MeSH terms
- Adenosine Triphosphate, Archaea, Bacteria, Bacterial Proteins, Carrier Proteins, N-Acetylneuraminic Acid, Membrane Transport Proteins
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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