Document Detail


Structure and mechanism of a bacterial sodium-dependent dicarboxylate transporter.
MedLine Citation:
PMID:  23086149     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Romina Mancusso; G Glenn Gregorio; Qun Liu; Da-Neng Wang
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-10-21
Journal Detail:
Title:  Nature     Volume:  491     ISSN:  1476-4687     ISO Abbreviation:  Nature     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-11-22     Completed Date:  2013-01-15     Revised Date:  2013-12-04    
Medline Journal Info:
Nlm Unique ID:  0410462     Medline TA:  Nature     Country:  England    
Other Details:
Languages:  eng     Pagination:  622-6     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
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:
P30 EB009998/EB/NIBIB NIH HHS; 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:
0/Dicarboxylic Acid Transporters; 2968PHW8QP/Citric Acid; 9NEZ333N27/Sodium
Comments/Corrections

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