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Reconstructing the transport cycle in the sugar porter superfamily using coevolution-powered machine learning
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). KTH Royal Institute of Technology, Sweden.ORCID iD: 0000-0002-6855-9295
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). KTH Royal Institute of Technology, Sweden.ORCID iD: 0000-0001-8595-9250
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). KTH Royal Institute of Technology, Sweden.ORCID iD: 0000-0001-6177-0701
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Number of Authors: 62023 (English)In: eLIFE, E-ISSN 2050-084X, Vol. 12, article id e84805Article in journal (Refereed) Published
Abstract [en]

Sugar porters (SPs) represent the largest group of secondary-active transporters. Some members, such as the glucose transporters (GLUTs), 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 analyzed 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.

Place, publisher, year, edition, pages
2023. Vol. 12, article id e84805
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Biophysics
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URN: urn:nbn:se:su:diva-223414DOI: 10.7554/eLife.84805ISI: 001071912700001PubMedID: 37405846Scopus ID: 2-s2.0-85164005539OAI: oai:DiVA.org:su-223414DiVA, id: diva2:1809136
Available from: 2023-11-02 Created: 2023-11-02 Last updated: 2023-11-06Bibliographically approved

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McComas, Sarah ElizabethAlleva, ClaudiaBonaccorsi, MartaDrew, David

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