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Raniolo_2022_jmolb_preprint
Preprint

Uracil/H+ symport by the FurE transporter challenges the rocking-bundle mechanism of transport in APC transporters

  • Zantza, Iliana Department of Pharmacy, National and Kapodistrian University of Athens, Greece
  • Papadaki, Georgia F. Department of Biology, National and Kapodistrian University of Athens, Greece
  • Raniolo, Stefano ORCID Euler Institute (EUL), Università della Svizzera italiana, Switzerland
  • Pyrris, Yiannis Department of Biology, National and Kapodistrian University of Athens, Greece
  • Lambrinidis, George Department of Pharmacy, National and Kapodistrian University of Athens, Greece
  • Limongelli, Vittorio ORCID Euler Institute (EUL), Università della Svizzera italiana, Switzerland - Department of Pharmacy, University of Naples “Federico II”, Italy
  • Diallinas, George Department of Biology, National and Kapodistrian University of Athens, Greece - Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, Heraklion, Greece
  • Mikros, Emmanuel Department of Pharmacy, National and Kapodistrian University of Athens, Greece - Athena Research and Innovation Center in Information Communication & Knowledge Technologies, Marousi, Greece
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  • 2022
Submitted to:
  • Journal of molecular biology. - 2022, vol. 435, no. 19, p. 168226
Aspergillus nidulans
NCS1
Fungal
Specificity
Structure-function
English Transporters mediate the uptake of solutes, metabolites and drugs across the cell membrane. The eukaryotic FurE nucleobase/H+ symporter of Aspergillus nidulans has been used as a model protein to address structure-function relationships in the APC transporter superfamily, members of which are characterized by the LeuT-fold and seem to operate by the so-called ‘rocking-bundle’ mechanism. In this study, we reveal the binding mode, translocation and release pathway of uracil/H+ by FurE, using path collective variable, funnel metadynamics and rationally designed mutational analysis. Our study reveals a step-wise, induced-fit, mechanism of ordered sequential transport of proton and uracil, which in turn suggests that the FurE symporter, and probably structurally similar transporters, functions as a multi-step gated pore, rather than employing ‘rocking’ of compact domains, as generally proposed for APC transporters. In addition, our work further supports the emerging concept that specific elements of cytosolic terminal regions of transporters might be functionally important.
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Language
  • English
Classification
Pharmacology, therapeutics, toxicology
License
Rights reserved
Open access status
green
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Persistent URL
https://n2t.net/ark:/12658/srd1328421
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