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L amino acid transporter structure and molecular bases for the asymmetry of substrate interaction

Author

Listed:
  • Ekaitz Errasti-Murugarren

    (Barcelona Institute of Science and Technology)

  • Joana Fort

    (Barcelona Institute of Science and Technology
    Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER)
    University of Barcelona)

  • Paola Bartoccioni

    (Barcelona Institute of Science and Technology
    Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER))

  • Lucía Díaz

    (Life Sciences Department)

  • Els Pardon

    (VIB-VUB Center for Structural Biology, Pleinlaan 2
    Vrije Universiteit Brussel, Pleinlaan 2)

  • Xavier Carpena

    (CELLS-ALBA Synchrotron Light Source)

  • Meritxell Espino-Guarch

    (Sidra Medicine)

  • Antonio Zorzano

    (Barcelona Institute of Science and Technology
    University of Barcelona
    Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM))

  • Christine Ziegler

    (Universität Regensburg)

  • Jan Steyaert

    (VIB-VUB Center for Structural Biology, Pleinlaan 2
    Vrije Universiteit Brussel, Pleinlaan 2)

  • Juan Fernández-Recio

    (Life Sciences Department)

  • Ignacio Fita

    (Barcelona Molecular Biology Institut (IBMB-CSIC) and Unit of Excellence María de Maeztu)

  • Manuel Palacín

    (Barcelona Institute of Science and Technology
    Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER)
    University of Barcelona)

Abstract

L-amino acid transporters (LATs) play key roles in human physiology and are implicated in several human pathologies. LATs are asymmetric amino acid exchangers where the low apparent affinity cytoplasmic side controls the exchange of substrates with high apparent affinity on the extracellular side. Here, we report the crystal structures of an LAT, the bacterial alanine-serine-cysteine exchanger (BasC), in a non-occluded inward-facing conformation in both apo and substrate-bound states. We crystallized BasC in complex with a nanobody, which blocks the transporter from the intracellular side, thus unveiling the sidedness of the substrate interaction of BasC. Two conserved residues in human LATs, Tyr 236 and Lys 154, are located in equivalent positions to the Na1 and Na2 sites of sodium-dependent APC superfamily transporters. Functional studies and molecular dynamics (MD) calculations reveal that these residues are key for the asymmetric substrate interaction of BasC and in the homologous human transporter Asc-1.

Suggested Citation

  • Ekaitz Errasti-Murugarren & Joana Fort & Paola Bartoccioni & Lucía Díaz & Els Pardon & Xavier Carpena & Meritxell Espino-Guarch & Antonio Zorzano & Christine Ziegler & Jan Steyaert & Juan Fernández-Re, 2019. "L amino acid transporter structure and molecular bases for the asymmetry of substrate interaction," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09837-z
    DOI: 10.1038/s41467-019-09837-z
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    Cited by:

    1. Josep Rullo-Tubau & Maria Martinez-Molledo & Paola Bartoccioni & Ignasi Puch-Giner & Ángela Arias & Suwipa Saen-Oon & Camille Stephan-Otto Attolini & Rafael Artuch & Lucía Díaz & Víctor Guallar & Ekai, 2024. "Structure and mechanisms of transport of human Asc1/CD98hc amino acid transporter," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    2. Yongchan Lee & Pattama Wiriyasermkul & Pornparn Kongpracha & Satomi Moriyama & Deryck J. Mills & Werner Kühlbrandt & Shushi Nagamori, 2022. "Ca2+-mediated higher-order assembly of heterodimers in amino acid transport system b0,+ biogenesis and cystinuria," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    3. Michael F. Fuss & Jan-Philip Wieferig & Robin A. Corey & Yvonne Hellmich & Igor Tascón & Joana S. Sousa & Phillip J. Stansfeld & Janet Vonck & Inga Hänelt, 2023. "Cyclic di-AMP traps proton-coupled K+ transporters of the KUP family in an inward-occluded conformation," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    4. Martin F. Peter & Jan A. Ruland & Peer Depping & Niels Schneberger & Emmanuele Severi & Jonas Moecking & Karl Gatterdam & Sarah Tindall & Alexandre Durand & Veronika Heinz & Jan Peter Siebrasse & Paul, 2022. "Structural and mechanistic analysis of a tripartite ATP-independent periplasmic TRAP transporter," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    5. Joanne L. Parker & Justin C. Deme & Dimitrios Kolokouris & Gabriel Kuteyi & Philip C. Biggin & Susan M. Lea & Simon Newstead, 2021. "Molecular basis for redox control by the human cystine/glutamate antiporter system xc−," Nature Communications, Nature, vol. 12(1), pages 1-11, December.

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