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PreprintCited by 11Drug Transport and Resistance MechanismsPlant Molecular Biology ResearchProtein Structure and Dynamics

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Restriction of access to the central cavity is a major contributor to substrate selectivity in plant ABCG transporters

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Pakuła, Konrad, Sequeiros-Borja, Carlos, Biała-Leonhard, Wanda, Pawela, Aleksandra, Banasiak, Joanna, Bailly, Aurélien, Radom, Marcin, Geisler, Markus, Brezovsky, Jan, Jasiński, Michał·2022·Cellular and Molecular Life Sciences
DOI 10.1101/2022.08.16.503940PMC PMC10036432

Preprint — published as 10.1007/s00018-023-04751-6 · Paper page

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Abstract

ABCG46 of the legume Medicago truncatula is an ABC-type transporter responsible for highly selective translocation of the phenylpropanoids, 4-coumarate and liquiritigenin, over the plasma membrane. To investigate molecular determinants of the observed substrate selectivity, we applied a combination of phylogenetic and biochemical analyses, AlphaFold2 structure prediction, molecular dynamics simulations, and mutagenesis. We discovered an unusually narrow transient access path to the central cavity of MtABCG46 that constitutes an initial filter responsible for the selective translocation of these phenylpropanoids through a lipid bilayer. Furthermore, we identified remote residue F562 as pivotal for maintaining the stability of this filter. The determination of individual amino acids that’ impact the selective transport of specialized metabolites may provide new opportunities associated with ABCGs being of interest, as a clinically relevant group of proteins.

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Metadata

Authors
Pakuła, K., Sequeiros-Borja, C., Biała-Leonhard, W., Pawela, A., Banasiak, J., Bailly, A., Radom, M., Geisler, M., Brezovsky, J., & Jasiński, M.
Affiliations
  • Institute of Bioorganic Chemistry, Polish Academy of Sciences (PL)
  • International Institute of Molecular and Cell Biology (PL)
  • University of Zurich (CH)
  • University of Fribourg (CH)
Corresponding author
Jasiński, Michał
ORCID
Venue
Cellular and Molecular Life Sciences
Publisher
openRxiv
Published
2022-08-16
Volume
80
Issue
4
Pages
105-105
ISSN
1420-682X (ISSN-L)
DOI
10.1101/2022.08.16.503940
PMC
PMC10036432
OpenAlex
W4360600047
Cited by
11
References
1
Citations by year
2026: 1 · 2025: 6 · 2024: 3 · 2023: 1
FWCI
1.34
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Cellular and Molecular Life Sciences (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, cc-by-nc-nd)
  • Zurich Open Repository and Archive (University of Zurich) (submittedVersion, cc-by)
  • Zurich Open Repository and Archive (University of Zurich)
Funders
  • Narodowe Centrum Nauki (2017/27/B/NZ1/01090, 2017/25/B/NZ1/01307)
  • Narodowym Centrum Nauki (2017/25/B/NZ1/01307)
  • Międzynarodowy Instytut Biologii Molekularnej i Komórkowej w Warszawie
  • Narodowe Centrum Badań i Rozwoju (POWR.03.02.00-00-1032/16, POWR.03.02.00-00-I022/16)
Topics
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
  • Life Sciences › Agricultural and Biological Sciences › Plant Science › Plant Molecular Biology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
Keywords
ABCG transporters, Medicago truncatula, substrate specificity, liquiritigenin, central cavity, access paths, lipid bilayers, secondary metabolites, plasma membrane transport
MeSH terms
ATP Binding Cassette Transporter, Subfamily G, Phylogeny, Mutagenesis, ATP-Binding Cassette Transporters, Molecular Dynamics Simulation

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