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

Ekaitz Errasti-Murugarren, Joana Fort, Paola Bartoccioni, Lucía Díaz, Els Pardon, Xavier Carpena, Meritxell Espino-Guarch, Antonio Zorzano, Christine Ziegler, Jan Steyaert, Juan Fernández-Recio, Ignacio Fita () and Manuel Palacín ()
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Ekaitz Errasti-Murugarren: Barcelona Institute of Science and Technology
Joana Fort: Barcelona Institute of Science and Technology
Paola Bartoccioni: Barcelona Institute of Science and Technology
Lucía Díaz: Life Sciences Department
Els Pardon: VIB-VUB Center for Structural Biology, Pleinlaan 2
Xavier Carpena: CELLS-ALBA Synchrotron Light Source
Meritxell Espino-Guarch: Sidra Medicine
Antonio Zorzano: Barcelona Institute of Science and Technology
Christine Ziegler: Universität Regensburg
Jan Steyaert: VIB-VUB Center for Structural Biology, 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

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-09837-z

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