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Nat Commun. 2019 Apr 18;10(1):1807. doi: 10.1038/s41467-019-09837-z.

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

Author information

1
Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology, 08028, Barcelona, Spain.
2
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 08028, Barcelona, Spain.
3
Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, University of Barcelona, 08028, Barcelona, Spain.
4
Barcelona Supercomputing Center (BSC), Joint BSC-CRG-IRB Research Program in Computational Biology, Life Sciences Department, 08034, Barcelona, Spain.
5
VIB-VUB Center for Structural Biology, Pleinlaan 2, 1050, Brussels, Belgium.
6
Structural Biology Brussels, Vrije Universiteit Brussel, Pleinlaan 2, 1050, Brussels, Belgium.
7
CELLS-ALBA Synchrotron Light Source, 08290, Barcelona, Spain.
8
Translational Medicine, Sidra Medicine, 26999, Doha, Qatar.
9
Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 08028, Barcelona, Spain.
10
Institute of Biophysics and Biophysical Chemistry, Universität Regensburg, 95053, Regensburg, Germany.
11
Barcelona Molecular Biology Institut (IBMB-CSIC) and Unit of Excellence María de Maeztu, 08028, Barcelona, Spain. ifrcri@ibmb.csic.es.
12
Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology, 08028, Barcelona, Spain. manuel.palacin@irbbarcelona.org.
13
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 08028, Barcelona, Spain. manuel.palacin@irbbarcelona.org.
14
Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, University of Barcelona, 08028, Barcelona, Spain. manuel.palacin@irbbarcelona.org.

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.

PMID:
31000719
PMCID:
PMC6472337
DOI:
10.1038/s41467-019-09837-z
[Indexed for MEDLINE]
Free PMC Article

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