Structural and mechanistic analysis of a tripartite ATP-independent periplasmic TRAP transporter
Open accessPublished version of a preprint
Abstract
Tripartite ATP-independent periplasmic (TRAP) transporters are found widely in bacteria and archaea and consist of three structural domains, a soluble substrate-binding protein (P-domain), and two transmembrane domains (Q- and M-domains). HiSiaPQM and its homologs are TRAP transporters for sialic acid and are essential for host colonization by pathogenic bacteria. Here, we reconstitute HiSiaQM into lipid nanodiscs and use cryo-EM to reveal the structure of a TRAP transporter. It is composed of 16 transmembrane helices that are unexpectedly structurally related to multimeric elevator-type transporters. The idiosyncratic Q-domain of TRAP transporters enables the formation of a monomeric elevator architecture. A model of the tripartite PQM complex is experimentally validated and reveals the coupling of the substrate-binding protein to the transporter domains. We use single-molecule total internal reflection fluorescence (TIRF) microscopy in solid-supported lipid bilayers and surface plasmon resonance to study the formation of the tripartite complex and to investigate the impact of interface mutants. Furthermore, we characterize high-affinity single variable domains on heavy chain (VHH) antibodies that bind to the periplasmic side of HiSiaQM and inhibit sialic acid uptake, providing insight into how TRAP transporter function might be inhibited in vivo.
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Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764 · see citing works
Can AlphaFold2 predict protein-peptide complex structures accurately?
Ko, J., & Lee, J. (2021) · doi:10.1101/2021.07.27.453972 · Cited by 83 · see citing works
Peter, M. F., Depping, P., Schneberger, N., Severi, E., Gatterdam, K., Tindall, S., Durand, A., Heinz, V., Koenig, P.-A., Geyer, M., et al. (2021) · doi:10.1101/2021.12.03.471092 · Cited by 38 · see citing works
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Peter, M. F., Depping, P., Schneberger, N., Severi, E., Gatterdam, K., Tindall, S., Durand, A., Heinz, V., Koenig, P.-A., Geyer, M., et al. (2021) · doi:10.1101/2021.12.03.471092 · Cited by 38 · see citing works
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- Authors
- Peter, M. F., Ruland, J. A., Depping, P., Schneberger, N., Severi, E., Moecking, J., Gatterdam, K., Tindall, S., Durand, A., Heinz, V., Siebrasse, J. P., Koenig, P.-A., Geyer, M., Ziegler, C., Kubitscheck, U., 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
- Published
- 2022-08-04
- Volume
- 13
- Issue
- 1
- Pages
- 4471-4471
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC9352664
- OpenAlex
- W4289841189
- Cited by
- 38
- References
- 3
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 18 · 2023: 11 · 2022: 1
- FWCI
- 3.76
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- 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
- Deutsche Forschungsgemeinschaft (EXC2151–390873048, 398967434 – TRR 261, HA 6805/4-1)
- 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
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