| Structure and mechanism of a bacterial sodium-dependent dicarboxylate transporter. | |
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MedLine Citation:
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PMID: 23086149 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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In human cells, cytosolic citrate is a chief precursor for the synthesis of fatty acids, triacylglycerols, cholesterol and low-density lipoprotein. Cytosolic citrate further regulates the energy balance of the cell by activating the fatty-acid-synthesis pathway while downregulating both the glycolysis and fatty-acid β-oxidation pathways. The rate of fatty-acid synthesis in liver and adipose cells, the two main tissue types for such synthesis, correlates directly with the concentration of citrate in the cytosol, with the cytosolic citrate concentration partially depending on direct import across the plasma membrane through the Na(+)-dependent citrate transporter (NaCT). Mutations of the homologous fly gene (Indy; I'm not dead yet) result in reduced fat storage through calorie restriction. More recently, Nact (also known as Slc13a5)-knockout mice have been found to have increased hepatic mitochondrial biogenesis, higher lipid oxidation and energy expenditure, and reduced lipogenesis, which taken together protect the mice from obesity and insulin resistance. To understand the transport mechanism of NaCT and INDY proteins, here we report the 3.2 Å crystal structure of a bacterial INDY homologue. One citrate molecule and one sodium ion are bound per protein, and their binding sites are defined by conserved amino acid motifs, forming the structural basis for understanding the specificity of the transporter. Comparison of the structures of the two symmetrical halves of the transporter suggests conformational changes that propel substrate translocation. |
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Authors:
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Romina Mancusso; G Glenn Gregorio; Qun Liu; Da-Neng Wang |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2012-10-21 |
Journal Detail:
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Title: Nature Volume: 491 ISSN: 1476-4687 ISO Abbreviation: Nature Publication Date: 2012 Nov |
Date Detail:
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Created Date: 2012-11-22 Completed Date: 2013-01-15 Revised Date: 2013-04-16 |
Medline Journal Info:
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Nlm Unique ID: 0410462 Medline TA: Nature Country: England |
Other Details:
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Languages: eng Pagination: 622-6 Citation Subset: IM |
Affiliation:
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The Helen L. and Martin S. Kimmel Center for Biology and Medicine at the Skirball Institute of Biomolecular Medicine, New York University School of Medicine, 540 First Avenue, New York, New York 10016, USA. |
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| MeSH Terms | |
Descriptor/Qualifier:
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Amino Acid Motifs Amino Acid Sequence Binding Sites Citric Acid / chemistry, metabolism Crystallography, X-Ray Dicarboxylic Acid Transporters / chemistry*, metabolism* Ion Transport Models, Molecular Molecular Sequence Data Protein Conformation Sodium / chemistry, metabolism Structural Homology, Protein Structure-Activity Relationship Vibrio cholerae / chemistry* |
| Grant Support | |
ID/Acronym/Agency:
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R01 DK053973/DK/NIDDK NIH HHS; R01 GM093825/GM/NIGMS NIH HHS; R01 MH083840/MH/NIMH NIH HHS; R01-DK073973/DK/NIDDK NIH HHS; R01-GM093825/GM/NIGMS NIH HHS; R01-MH083840/MH/NIMH NIH HHS; U54 GM075026/GM/NIGMS NIH HHS; U54-GM075026/GM/NIGMS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Dicarboxylic Acid Transporters; 7440-23-5/Sodium; 77-92-9/Citric Acid |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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