Chloride binding site of neurotransmitter sodium symporters
Neurotransmitter:sodium symporters (NSSs) play a critical role in signaling by reuptake of neurotransmitters. Eukaryotic NSSs are chloride-dependent, whereas prokaryotic NSS homologs like LeuT are chloride-independent but contain an acidic residue (Glu290 in LeuT) at a site where eukaryotic NSSs hav...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2013-05, Vol.110 (21), p.8489-8494 |
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| container_title | Proceedings of the National Academy of Sciences - PNAS |
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| creator | Kantcheva, Adriana K. Quick, Matthias Shi, Lei Winther, Anne-Marie Lund Stolzenberg, Sebastian Weinstein, Harel Javitch, Jonathan A. Nissen, Poul |
| description | Neurotransmitter:sodium symporters (NSSs) play a critical role in signaling by reuptake of neurotransmitters. Eukaryotic NSSs are chloride-dependent, whereas prokaryotic NSS homologs like LeuT are chloride-independent but contain an acidic residue (Glu290 in LeuT) at a site where eukaryotic NSSs have a serine. The LeuT-E290S mutant displays chloride-dependent activity. We show that, in LeuT-E290S cocrystallized with bromide or chloride, the anion is coordinated by side chain hydroxyls from Tyr47, Ser290, and Thr254 and the side chain amide of Gln250. The bound anion and the nearby sodium ion in the Na1 site organize a connection between their coordinating residues and the extracellular gate of LeuT through a continuous H-bond network. The specific insights from the structures, combined with results from substrate binding studies and molecular dynamics simulations, reveal an anion-dependent occlusion mechanism for NSS and shed light on the functional role of chloride binding. |
| doi_str_mv | 10.1073/pnas.1221279110 |
| format | Article |
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Eukaryotic NSSs are chloride-dependent, whereas prokaryotic NSS homologs like LeuT are chloride-independent but contain an acidic residue (Glu290 in LeuT) at a site where eukaryotic NSSs have a serine. The LeuT-E290S mutant displays chloride-dependent activity. We show that, in LeuT-E290S cocrystallized with bromide or chloride, the anion is coordinated by side chain hydroxyls from Tyr47, Ser290, and Thr254 and the side chain amide of Gln250. The bound anion and the nearby sodium ion in the Na1 site organize a connection between their coordinating residues and the extracellular gate of LeuT through a continuous H-bond network. The specific insights from the structures, combined with results from substrate binding studies and molecular dynamics simulations, reveal an anion-dependent occlusion mechanism for NSS and shed light on the functional role of chloride binding.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1221279110</identifier><identifier>PMID: 23641004</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Amino acids ; Anions ; Bacteria - chemistry ; Bacteria - metabolism ; Bacterial Proteins - chemistry ; Bacterial Proteins - metabolism ; Binding Sites ; Biological Sciences ; Bromides - chemistry ; Bromides - metabolism ; Chlorides ; Chlorides - chemistry ; Chlorides - metabolism ; Crystal structure ; Crystallography, X-Ray ; Ions ; molecular dynamics ; Molecules ; mutants ; Neurotransmitters ; Plasma Membrane Neurotransmitter Transport Proteins - chemistry ; Plasma Membrane Neurotransmitter Transport Proteins - metabolism ; Prokaryotes ; serine ; Serotonin plasma membrane transport proteins ; Simulation ; Sodium ; Symporters</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2013-05, Vol.110 (21), p.8489-8494</ispartof><rights>copyright © 1993-2008 National Academy of Sciences of the United States of America</rights><rights>Copyright National Academy of Sciences May 21, 2013</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c590t-73dfb9fa01a25b5b9960fddb3f10acb3bb62a5927de2b63866fec1678f9b6a383</citedby><cites>FETCH-LOGICAL-c590t-73dfb9fa01a25b5b9960fddb3f10acb3bb62a5927de2b63866fec1678f9b6a383</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/110/21.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/42656750$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/42656750$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,723,776,780,799,881,27901,27902,53766,53768,57992,58225</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23641004$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kantcheva, Adriana K.</creatorcontrib><creatorcontrib>Quick, Matthias</creatorcontrib><creatorcontrib>Shi, Lei</creatorcontrib><creatorcontrib>Winther, Anne-Marie Lund</creatorcontrib><creatorcontrib>Stolzenberg, Sebastian</creatorcontrib><creatorcontrib>Weinstein, Harel</creatorcontrib><creatorcontrib>Javitch, Jonathan A.</creatorcontrib><creatorcontrib>Nissen, Poul</creatorcontrib><title>Chloride binding site of neurotransmitter sodium symporters</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Neurotransmitter:sodium symporters (NSSs) play a critical role in signaling by reuptake of neurotransmitters. Eukaryotic NSSs are chloride-dependent, whereas prokaryotic NSS homologs like LeuT are chloride-independent but contain an acidic residue (Glu290 in LeuT) at a site where eukaryotic NSSs have a serine. The LeuT-E290S mutant displays chloride-dependent activity. We show that, in LeuT-E290S cocrystallized with bromide or chloride, the anion is coordinated by side chain hydroxyls from Tyr47, Ser290, and Thr254 and the side chain amide of Gln250. The bound anion and the nearby sodium ion in the Na1 site organize a connection between their coordinating residues and the extracellular gate of LeuT through a continuous H-bond network. The specific insights from the structures, combined with results from substrate binding studies and molecular dynamics simulations, reveal an anion-dependent occlusion mechanism for NSS and shed light on the functional role of chloride binding.</description><subject>Amino acids</subject><subject>Anions</subject><subject>Bacteria - chemistry</subject><subject>Bacteria - metabolism</subject><subject>Bacterial Proteins - chemistry</subject><subject>Bacterial Proteins - metabolism</subject><subject>Binding Sites</subject><subject>Biological Sciences</subject><subject>Bromides - chemistry</subject><subject>Bromides - metabolism</subject><subject>Chlorides</subject><subject>Chlorides - chemistry</subject><subject>Chlorides - metabolism</subject><subject>Crystal structure</subject><subject>Crystallography, X-Ray</subject><subject>Ions</subject><subject>molecular dynamics</subject><subject>Molecules</subject><subject>mutants</subject><subject>Neurotransmitters</subject><subject>Plasma Membrane Neurotransmitter Transport Proteins - chemistry</subject><subject>Plasma Membrane Neurotransmitter Transport Proteins - metabolism</subject><subject>Prokaryotes</subject><subject>serine</subject><subject>Serotonin plasma membrane transport proteins</subject><subject>Simulation</subject><subject>Sodium</subject><subject>Symporters</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkU1v1DAURS1ERYfCmhUQiQ2btM928mILCQmNWqhUiQV0bdmJPfUoiQc7Qeq_x-kMw8emK0v28fH1u4S8onBOoeEXu1Gnc8oYZY2kFJ6QFQVJS6wkPCUrANaUomLVKXme0hYAZC3gGTllHCsKUK3Ih_VdH6LvbGH82PlxUyQ_2SK4YrRzDFPUYxr8NNlYpND5eSjS_bALMW-kF-TE6T7Zl4f1jNxeXX5ffylvvn6-Xn-6KdtawlQ2vHNGOg1Us9rURkoE13WGOwq6NdwYZLqWrOksM8gForMtxUY4aVBzwc_Ix713N5vBdq0dc6xe7aIfdLxXQXv178no79Qm_FQcEZsKs-D9QRDDj9mmSQ0-tbbv9WjDnBQVwPPcBPLHUV5XjWRYQ0bf_YduwxzHPImFQmBIa5mpiz3VxpBStO6Ym4JaOlRLh-pPh_nGm7-_e-R_l5aBtwdguXnUZR-jSlRiefT1ntimKcQjUuXc2DxEPxicDkpvok_q9hsDigCUC8Yk_wUylrVi</recordid><startdate>20130521</startdate><enddate>20130521</enddate><creator>Kantcheva, Adriana K.</creator><creator>Quick, Matthias</creator><creator>Shi, Lei</creator><creator>Winther, Anne-Marie Lund</creator><creator>Stolzenberg, Sebastian</creator><creator>Weinstein, Harel</creator><creator>Javitch, Jonathan A.</creator><creator>Nissen, Poul</creator><general>National Academy of Sciences</general><general>National Acad Sciences</general><scope>FBQ</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>7S9</scope><scope>L.6</scope><scope>5PM</scope></search><sort><creationdate>20130521</creationdate><title>Chloride binding site of neurotransmitter sodium symporters</title><author>Kantcheva, Adriana K. ; Quick, Matthias ; Shi, Lei ; Winther, Anne-Marie Lund ; Stolzenberg, Sebastian ; Weinstein, Harel ; Javitch, Jonathan A. ; Nissen, Poul</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c590t-73dfb9fa01a25b5b9960fddb3f10acb3bb62a5927de2b63866fec1678f9b6a383</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Amino acids</topic><topic>Anions</topic><topic>Bacteria - chemistry</topic><topic>Bacteria - metabolism</topic><topic>Bacterial Proteins - chemistry</topic><topic>Bacterial Proteins - metabolism</topic><topic>Binding Sites</topic><topic>Biological Sciences</topic><topic>Bromides - chemistry</topic><topic>Bromides - metabolism</topic><topic>Chlorides</topic><topic>Chlorides - chemistry</topic><topic>Chlorides - metabolism</topic><topic>Crystal structure</topic><topic>Crystallography, X-Ray</topic><topic>Ions</topic><topic>molecular dynamics</topic><topic>Molecules</topic><topic>mutants</topic><topic>Neurotransmitters</topic><topic>Plasma Membrane Neurotransmitter Transport Proteins - chemistry</topic><topic>Plasma Membrane Neurotransmitter Transport Proteins - metabolism</topic><topic>Prokaryotes</topic><topic>serine</topic><topic>Serotonin plasma membrane transport proteins</topic><topic>Simulation</topic><topic>Sodium</topic><topic>Symporters</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kantcheva, Adriana K.</creatorcontrib><creatorcontrib>Quick, Matthias</creatorcontrib><creatorcontrib>Shi, Lei</creatorcontrib><creatorcontrib>Winther, Anne-Marie Lund</creatorcontrib><creatorcontrib>Stolzenberg, Sebastian</creatorcontrib><creatorcontrib>Weinstein, Harel</creatorcontrib><creatorcontrib>Javitch, Jonathan A.</creatorcontrib><creatorcontrib>Nissen, Poul</creatorcontrib><collection>AGRIS</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>AGRICOLA</collection><collection>AGRICOLA - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kantcheva, Adriana K.</au><au>Quick, Matthias</au><au>Shi, Lei</au><au>Winther, Anne-Marie Lund</au><au>Stolzenberg, Sebastian</au><au>Weinstein, Harel</au><au>Javitch, Jonathan A.</au><au>Nissen, Poul</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Chloride binding site of neurotransmitter sodium symporters</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2013-05-21</date><risdate>2013</risdate><volume>110</volume><issue>21</issue><spage>8489</spage><epage>8494</epage><pages>8489-8494</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>Neurotransmitter:sodium symporters (NSSs) play a critical role in signaling by reuptake of neurotransmitters. Eukaryotic NSSs are chloride-dependent, whereas prokaryotic NSS homologs like LeuT are chloride-independent but contain an acidic residue (Glu290 in LeuT) at a site where eukaryotic NSSs have a serine. The LeuT-E290S mutant displays chloride-dependent activity. We show that, in LeuT-E290S cocrystallized with bromide or chloride, the anion is coordinated by side chain hydroxyls from Tyr47, Ser290, and Thr254 and the side chain amide of Gln250. The bound anion and the nearby sodium ion in the Na1 site organize a connection between their coordinating residues and the extracellular gate of LeuT through a continuous H-bond network. The specific insights from the structures, combined with results from substrate binding studies and molecular dynamics simulations, reveal an anion-dependent occlusion mechanism for NSS and shed light on the functional role of chloride binding.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>23641004</pmid><doi>10.1073/pnas.1221279110</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Amino acids Anions Bacteria - chemistry Bacteria - metabolism Bacterial Proteins - chemistry Bacterial Proteins - metabolism Binding Sites Biological Sciences Bromides - chemistry Bromides - metabolism Chlorides Chlorides - chemistry Chlorides - metabolism Crystal structure Crystallography, X-Ray Ions molecular dynamics Molecules mutants Neurotransmitters Plasma Membrane Neurotransmitter Transport Proteins - chemistry Plasma Membrane Neurotransmitter Transport Proteins - metabolism Prokaryotes serine Serotonin plasma membrane transport proteins Simulation Sodium Symporters |
| title | Chloride binding site of neurotransmitter sodium symporters |
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