Structural basis for substrate binding and specificity of a sodium–alanine symporter AgcS

The amino acid, polyamine, and organocation (APC) superfamily is the second largest superfamily of membrane proteins forming secondary transporters that move a range of organic molecules across the cell membrane. Each transporter in the APC superfamily is specific for a unique subset of substrates,...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2019-02, Vol.116 (6), p.2086-2090
Main Authors: Ma, Jinming, Lei, Hsiang-Ting, Reyes, Francis E., Sanchez-Martinez, Silvia, Sarhan, Maen F., Hattne, Johan, Gonen, Tamir
Format: Article
Language:English
Subjects:
Alanine
Amino Acid Transport Systems, Neutral - chemistry
Amino Acid Transport Systems, Neutral - genetics
Amino Acid Transport Systems, Neutral - metabolism
Amino Acids
BASIC BIOLOGICAL SCIENCES
Binding Sites
Biological Sciences
Cell membranes
Crystal structure
D-Alanine
Glycine
Leucine
membrane protein
Membrane proteins
Models, Molecular
Mutation
Organic chemistry
Protein Binding
Protein Conformation
Proteins
Recombinant Proteins
secondary transporter
Selectivity
Site-directed mutagenesis
Sodium
specificity
Structural analysis
Structure-Activity Relationship
substrate binding
Substrate Specificity
Substrates
Symporters - chemistry
Symporters - genetics
Symporters - metabolism
Valine
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Summary:The amino acid, polyamine, and organocation (APC) superfamily is the second largest superfamily of membrane proteins forming secondary transporters that move a range of organic molecules across the cell membrane. Each transporter in the APC superfamily is specific for a unique subset of substrates, even if they possess a similar structural fold. The mechanism of substrate selectivity remains, by and large, elusive. Here, we report two crystal structures of an APC member from Methanococcus maripaludis, the alanine or glycine:cation symporter (AgcS), with L- or D-alanine bound. Structural analysis combined with site-directed mutagenesis and functional studies inform on substrate binding, specificity, and modulation of the AgcS family and reveal key structural features that allow this transporter to accommodate glycine and alanine while excluding all other amino acids. Mutation of key residues in the substrate binding site expand the selectivity to include valine and leucine. These studies provide initial insights into substrate selectivity in AgcS symporters.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1806206116