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PreprintCited by 31Protein Structure and DynamicsEnzyme Structure and FunctionDrug Transport and Resistance Mechanisms

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Reconstructing the transport cycle in the sugar porter superfamily using coevolution-powered machine learning

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Mitrovic, Darko, Comas, Sarah Mc, Alleva, Claudia, Bonaccorsi, Marta, Drew, David, Delemotte, Lucie·2022·eLife
DOI 10.1101/2022.09.24.509294PMC PMC10322152

Preprint — published as 10.7554/elife.84805 · Paper page

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Abstract

Sugar porters represent the largest group of secondary-active transporters. Some members, such as the glucose (GLUT) transporters, are well-known for their role in maintaining blood glucose homeostasis in mammals, with their expression upregulated in many types of cancers. Because only a few sugar porter structures have been determined, mechanistic models have been constructed by piecing together structural states of distantly related proteins. Current GLUT transport models are predominantly descriptive and oversimplified. Here, we have combined coevolution analysis and comparative modeling, to predict structures of the entire sugar porter superfamily in each state of the transport cycle. We have analysed the state-specific contacts inferred from coevolving residue pairs and shown how this information can be used to rapidly generate free-energy landscapes consistent with experimental estimates, as illustrated here for the mammalian fructose transporter GLUT5. By comparing many different sugar porter models and scrutinizing their sequence, we have been able to define the molecular determinants of the transport cycle, which are conserved throughout the sugar porter superfamily. We have also been able to highlight differences leading to the emergence of proton-coupling, validating, and extending the previously proposed latch mechanism. Our computational approach is transferable to any transporter, and to other protein families in general.

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Metadata

Authors
Mitrovic, D., Comas, S. M., Alleva, C., Bonaccorsi, M., Drew, D., & Delemotte, L.
Affiliations
  • Science for Life Laboratory (SE)
  • Stockholm University (SE)
Corresponding author
Delemotte, Lucie
ORCID
Venue
eLife
Publisher
openRxiv
Published
2022-09-26
Volume
12
ISSN
2050-084X (ISSN-L)
DOI
10.1101/2022.09.24.509294
PMC
PMC10322152
OpenAlex
W4383186916
Cited by
31
References
2
Citations by year
2026: 8 · 2025: 7 · 2024: 7 · 2023: 8 · 2022: 1
FWCI
2.66
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • eLife (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Göran Gustafssons Stiftelser
  • Knut och Alice Wallenbergs Stiftelse
  • Vetenskapsrådet (2019-02433, VR 2019)
  • Science for Life Laboratory
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
Keywords
GLUT5, fructose transporter, transport cycle, comparative protein modeling, free energy landscape, latching mechanism, proton-coupled transport, secondary active transporters, glucose transporters, cancer
MeSH terms
Sugars, Animals, Biological Transport, Glucose, Mammals, Membrane Transport Proteins, Glucose Transport Proteins, Facilitative

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