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

Abstract

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.

Authors:
; ; ; ; ; ORCiD logo;
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
National Institutes of Health (NIH)
OSTI Identifier:
1558316
Resource Type:
Journal Article
Journal Name:
Proceedings of the National Academy of Sciences of the United States of America
Additional Journal Information:
Journal Volume: 116; Journal Issue: 6; Journal ID: ISSN 0027-8424
Publisher:
National Academy of Sciences, Washington, DC (United States)
Country of Publication:
United States
Language:
ENGLISH

Citation Formats

Ma, Jinming, Lei, Hsiang-Ting, Reyes, Francis E., Sanchez-Martinez, Silvia, Sarhan, Maen F., Hattne, Johan, and Gonen, Tamir. Structural basis for substrate binding and specificity of a sodium–alanine symporter AgcS. United States: N. p., 2019. Web. doi:10.1073/pnas.1806206116.
Ma, Jinming, Lei, Hsiang-Ting, Reyes, Francis E., Sanchez-Martinez, Silvia, Sarhan, Maen F., Hattne, Johan, & Gonen, Tamir. Structural basis for substrate binding and specificity of a sodium–alanine symporter AgcS. United States. doi:10.1073/pnas.1806206116.
Ma, Jinming, Lei, Hsiang-Ting, Reyes, Francis E., Sanchez-Martinez, Silvia, Sarhan, Maen F., Hattne, Johan, and Gonen, Tamir. Fri . "Structural basis for substrate binding and specificity of a sodium–alanine symporter AgcS". United States. doi:10.1073/pnas.1806206116.
@article{osti_1558316,
title = {Structural basis for substrate binding and specificity of a sodium–alanine symporter AgcS},
author = {Ma, Jinming and Lei, Hsiang-Ting and Reyes, Francis E. and Sanchez-Martinez, Silvia and Sarhan, Maen F. and Hattne, Johan and Gonen, Tamir},
abstractNote = {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.},
doi = {10.1073/pnas.1806206116},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
issn = {0027-8424},
number = 6,
volume = 116,
place = {United States},
year = {2019},
month = {1}
}