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

Ma, Jinming; Lei, Hsiang-Ting; Reyes, Francis E.; Sanchez-Martinez, Silvia; Sarhan, Maen F.; Hattne, Johan; Gonen, Tamir

doi:10.1073/pnas.1806206116

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

Journal Article · Fri Jan 18 00:00:00 EST 2019 · Proceedings of the National Academy of Sciences of the United States of America

DOI:https://doi.org/10.1073/pnas.1806206116· OSTI ID:1558316

Ma, Jinming ^[1]; Lei, Hsiang-Ting ^[1]; Reyes, Francis E. ^[1]; Sanchez-Martinez, Silvia ^[1]; Sarhan, Maen F. ^[1];

^[2]; Gonen, Tamir ^[2]

Howard Hughes Medical Inst., Ashburn, VA (United States)
Howard Hughes Medical Inst., Ashburn, VA (United States); Univ. of California, Los Angeles, CA (United States)

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. As such, 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.

View Accepted Manuscript (DOE)

Cite

Export

Save

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS); Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States). Advanced Light Source (ALS)

Sponsoring Organization:: National Institutes of Health (NIH); National Institute of General Medical Sciences (NIGMS); Howard Hughes Medical Institute; USDOE Office of Science (SC)

Grant/Contract Number:: AC02-05CH11231; P41 GM103403; S10 RR029205; AC02-06CH11357

OSTI ID:: 1558316

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Vol. 116, Issue 6; ISSN 0027-8424

Publisher:: National Academy of SciencesCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

Citation Metrics:

Cited by: 12 works

Citation information provided by
Web of Science

References (31)

X-ray structures of LeuT in substrate-free outward-open and apo inward-open states Krishnamurthy, Harini; Gouaux, Eric Nature, Vol. 481, Issue 7382 https://doi.org/10.1038/nature10737	journal	January 2012
Characterization of Methanococcus maripaludis sp. nov., a new methanogen isolated from salt marsh sediment Jones, W. Jack; Paynter, M. J. B.; Gupta, R. Archives of Microbiology, Vol. 135, Issue 2 https://doi.org/10.1007/BF00408015	journal	January 1983
Regulatory Response of Methanococcus maripaludis to Alanine, an Intermediate Nitrogen Source Lie, T. J.; Leigh, J. A. Journal of Bacteriology, Vol. 184, Issue 19 https://doi.org/10.1128/JB.184.19.5301-5306.2002	journal	October 2002
The amino acid/polyamine/organocation (APC) superfamily of transporters specific for amino acids, polyamines and organocations Paulsen, Ian T.; Jack, Donald L.; Saier, Milton H. Microbiology, Vol. 146, Issue 8 https://doi.org/10.1099/00221287-146-8-1797	journal	August 2000
The Amino Acid-Polyamine-Organocation Superfamily Wong, Foon H.; Chen, Jonathan S.; Reddy, Vamsee Journal of Molecular Microbiology and Biotechnology, Vol. 22, Issue 2 https://doi.org/10.1159/000338542	journal	January 2012
The Crystal Structure of a Sodium Galactose Transporter Reveals Mechanistic Insights into Na+/Sugar Symport Faham, S.; Watanabe, A.; Besserer, G. M. Science, Vol. 321, Issue 5890 https://doi.org/10.1126/science.1160406	journal	August 2008
Expansion of the APC superfamily of secondary carriers: Expansion of the APC Superfamily of Secondary Carriers Vastermark, Ake; Wollwage, Simon; Houle, Michael E. Proteins: Structure, Function, and Bioinformatics, Vol. 82, Issue 10 https://doi.org/10.1002/prot.24643	journal	July 2014
Evolutionary relationship between 5+5 and 7+7 inverted repeat folds within the amino acid-polyamine-organocation superfamily: Evolutionary Relationship of Inverted Repeat Folds Västermark, Åke; Saier, Milton H. Proteins: Structure, Function, and Bioinformatics, Vol. 82, Issue 2 https://doi.org/10.1002/prot.24401	journal	October 2013
The Transporter Classification Database (TCDB): recent advances Saier, Milton H.; Reddy, Vamsee S.; Tsu, Brian V. Nucleic Acids Research, Vol. 44, Issue D1 https://doi.org/10.1093/nar/gkv1103	journal	November 2015
Structure and Mechanism of an Amino Acid Antiporter Gao, X.; Lu, F.; Zhou, L. Science, Vol. 324, Issue 5934 https://doi.org/10.1126/science.1173654	journal	May 2009
Identification of additional TnrA-regulated genes of Bacillus subtilis associated with a TnrA box: TnrA box-associated genes of Bacillus subtilis Yoshida, Ken-ichi; Yamaguchi, Hirotake; Kinehara, Masaki Molecular Microbiology, Vol. 49, Issue 1 https://doi.org/10.1046/j.1365-2958.2003.03567.x	journal	June 2003
Structure of a prokaryotic virtual proton pump at 3.2 Å resolution Fang, Yiling; Jayaram, Hariharan; Shane, Tania Nature, Vol. 460, Issue 7258 https://doi.org/10.1038/nature08201	journal	July 2009
Unlocking the molecular secrets of sodium-coupled transporters Krishnamurthy, Harini; Piscitelli, Chayne L.; Gouaux, Eric Nature, Vol. 459, Issue 7245 https://doi.org/10.1038/nature08143	journal	May 2009
The Solute Carrier Families Have a Remarkably Long Evolutionary History with the Majority of the Human Families Present before Divergence of Bilaterian Species Hoglund, P. J.; Nordstrom, K. J. V.; Schioth, H. B. Molecular Biology and Evolution, Vol. 28, Issue 4 https://doi.org/10.1093/molbev/msq350	journal	December 2010
Mechanism of substrate recognition and transport by an amino acid antiporter Gao, Xiang; Zhou, Lijun; Jiao, Xuyao Nature, Vol. 463, Issue 7282 https://doi.org/10.1038/nature08741	journal	January 2010
Classification Systems of Secondary Active Transporters Perland, Emelie; Fredriksson, Robert Trends in Pharmacological Sciences, Vol. 38, Issue 3 https://doi.org/10.1016/j.tips.2016.11.008	journal	March 2017
Crystal structure of a bacterial homologue of Na+/Cl--dependent neurotransmitter transporters Yamashita, Atsuko; Singh, Satinder K.; Kawate, Toshimitsu Nature, Vol. 437, Issue 7056 https://doi.org/10.1038/nature03978	journal	July 2005
Structure and Mechanism of a Na+-Independent Amino Acid Transporter Shaffer, P. L.; Goehring, A.; Shankaranarayanan, A. Science, Vol. 325, Issue 5943 https://doi.org/10.1126/science.1176088	journal	July 2009
Shared Molecular Mechanisms of Membrane Transporters Drew, David; Boudker, Olga Annual Review of Biochemistry, Vol. 85, Issue 1 https://doi.org/10.1146/annurev-biochem-060815-014520	journal	June 2016
D-Amino Acids Govern Stationary Phase Cell Wall Remodeling in Bacteria Lam, H.; Oh, D. -C.; Cava, F. Science, Vol. 325, Issue 5947 https://doi.org/10.1126/science.1178123	journal	September 2009
A Highly Conserved Bacterial D-Serine Uptake System Links Host Metabolism and Virulence Connolly, James P. R.; Gabrielsen, Mads; Goldstone, Robert J. PLOS Pathogens, Vol. 12, Issue 1 https://doi.org/10.1371/journal.ppat.1005359	journal	January 2016
Molecular basis of transport and regulation in the Na+/betaine symporter BetP Ressl, Susanne; Terwisscha van Scheltinga, Anke C.; Vonrhein, Clemens Nature, Vol. 458, Issue 7234 https://doi.org/10.1038/nature07819	journal	March 2009
A Competitive Inhibitor Traps LeuT in an Open-to-Out Conformation Singh, S. K.; Piscitelli, C. L.; Yamashita, A. Science, Vol. 322, Issue 5908 https://doi.org/10.1126/science.1166777	journal	December 2008
Common Folds and Transport Mechanisms of Secondary Active Transporters Shi, Yigong Annual Review of Biophysics, Vol. 42, Issue 1 https://doi.org/10.1146/annurev-biophys-083012-130429	journal	May 2013
Metabolic processes of Methanococcus maripaludis and potential applications Goyal, Nishu; Zhou, Zhi; Karimi, Iftekhar A. Microbial Cell Factories, Vol. 15, Issue 1 https://doi.org/10.1186/s12934-016-0500-0	journal	June 2016
Overexpression of the Alanine Carrier Protein Gene from Thermophilic Bacterium PS3 in Escherichia coli Kanamori, M.; Kamata, H.; Yagisawa, H. Journal of Biochemistry, Vol. 125, Issue 3 https://doi.org/10.1093/oxfordjournals.jbchem.a022308	journal	March 1999
The mechanism of sodium and substrate release from the binding pocket of vSGLT Watanabe, Akira; Choe, Seungho; Chaptal, Vincent Nature, Vol. 468, Issue 7326 https://doi.org/10.1038/nature09580	journal	December 2010
Structure and Molecular Mechanism of a Nucleobase-Cation-Symport-1 Family Transporter Weyand, S.; Shimamura, T.; Yajima, S. Science, Vol. 322, Issue 5902 https://doi.org/10.1126/science.1164440	journal	October 2008
Functional characterization of a member of alanine or glycine: cation symporter family in halotolerant cyanobacterium Aphanothece halophytica Bualuang, Aporn; Kageyama, Hakuto; Tanaka, Yoshito Bioscience, Biotechnology, and Biochemistry, Vol. 79, Issue 2 https://doi.org/10.1080/09168451.2014.968091	journal	October 2014
Antidepressant binding site in a bacterial homologue of neurotransmitter transporters Singh, Satinder K.; Yamashita, Atsuko; Gouaux, Eric Nature, Vol. 448, Issue 7156 https://doi.org/10.1038/nature06038	journal	August 2007
Primary structure of the alanine carrier protein of thermophilic bacterium PS3. Kamata, H.; Akiyama, S.; Morosawa, H. Journal of Biological Chemistry, Vol. 267, Issue 30 https://doi.org/10.1016/S0021-9258(19)36661-X	journal	October 1992

Cited By (5)

Structural basis of proton-coupled potassium transport in the KUP family Tascón, Igor; Sousa, Joana S.; Corey, Robin A. Nature Communications, Vol. 11, Issue 1 https://doi.org/10.1038/s41467-020-14441-7	journal	January 2020
Faster Simulations with a 5 fs Time Step for Lipids in the CHARMM Force Field Olesen, Karina; Awasthi, Neha; Bruhn, Dennis S. Journal of Chemical Theory and Computation, Vol. 14, Issue 6 https://doi.org/10.1021/acs.jctc.8b00267	journal	May 2018
Comparative structure, dynamics and evolution of acyl-carrier proteins from Borrelia burgdorferi, Brucella melitensis and Rickettsia prowazekii Barnwal, Ravi P.; Kaur, Mandeep; Heckert, Alec Biochemical Journal, Vol. 477, Issue 2 https://doi.org/10.1042/bcj20190797	journal	January 2020
Binding and transport of D-aspartate by the glutamate transporter homolog GltTk Arkhipova, Valentina; Trinco, Gianluca; Ettema, Thijs W. eLife, Vol. 8 https://doi.org/10.7554/elife.45286	journal	April 2019
Structure and mechanism of a redesigned multidrug transporter from the Major Facilitator Superfamily Wu, Hsin-Hui; Symersky, Jindrich; Lu, Min Scientific Reports, Vol. 10, Issue 1 https://doi.org/10.1038/s41598-020-60332-8	journal	March 2020

Similar Records

Substrate-Na{sup +} complex formation: Coupling mechanism for {gamma}-aminobutyrate symporters

Journal Article · Fri Jul 24 00:00:00 EDT 2009 · Biochemical and Biophysical Research Communications · OSTI ID:1558316

Pallo, Anna; Simon, Agnes; Bencsura, Akos; +2 more

Structure of the human cation–chloride cotransport KCC1 in an outward-open state

Journal Article · Mon Jun 27 00:00:00 EDT 2022 · Proceedings of the National Academy of Sciences of the United States of America · OSTI ID:1558316

Zhao, Yongxiang; Shen, Jiemin; Wang, Qinzhe; +5 more

Structural basis for divergent and convergent evolution of catalytic machineries in plant aromatic amino acid decarboxylase proteins

Journal Article · Tue May 05 00:00:00 EDT 2020 · Proceedings of the National Academy of Sciences of the United States of America · OSTI ID:1558316

Torrens-Spence, Michael P.; Chiang, Ying-Chih; Smith, Tyler; +3 more

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
secondary transporter
substrate binding
specificity
membrane protein
crystal structure

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

Citation Formats

References (31)

Cited By (5)

Similar Records

Related Subjects