Structural basis of the alternating-access mechanism in a bile acid transporter.
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| Title: | Structural basis of the alternating-access mechanism in a bile acid transporter. |
|---|---|
| Authors: | Zhou, Xiaoming, Levin, Elena J., Pan, Yaping, McCoy, Jason G., Sharma, Ruchika, Kloss, Brian, Bruni, Renato, Quick, Matthias, Zhou, Ming |
| Source: | Nature. 1/23/2014, Vol. 505 Issue 7484, p569-573. 5p. |
| Subjects: | Bile acids, Cholesterol, Liver cells, Secretion, Enterohepatic circulation, Fat-soluble vitamins, Intestinal physiology |
| Abstract: | Bile acids are synthesized from cholesterol in hepatocytes and secreted through the biliary tract into the small intestine, where they aid in absorption of lipids and fat-soluble vitamins. Through a process known as enterohepatic recirculation, more than 90% of secreted bile acids are then retrieved from the intestine and returned to the liver for resecretion. In humans, there are two Na+-dependent bile acid transporters involved in enterohepatic recirculation, the Na+-taurocholate co-transporting polypeptide (NTCP; also known as SLC10A1) expressed in hepatocytes, and the apical sodium-dependent bile acid transporter (ASBT; also known as SLC10A2) expressed on enterocytes in the terminal ileum. In recent years, ASBT has attracted much interest as a potential drug target for treatment of hypercholesterolaemia, because inhibition of ASBT reduces reabsorption of bile acids, thus increasing bile acid synthesis and consequently cholesterol consumption. However, a lack of three-dimensional structures of bile acid transporters hampers our ability to understand the molecular mechanisms of substrate selectivity and transport, and to interpret the wealth of existing functional data. The crystal structure of an ASBT homologue from Neisseria meningitidis (ASBTNM) in detergent was reported recently, showing the protein in an inward-open conformation bound to two Na+ and a taurocholic acid. However, the structural changes that bring bile acid and Na+ across the membrane are difficult to infer from a single structure. To understand the structural changes associated with the coupled transport of Na+ and bile acids, here we solved two structures of an ASBT homologue from Yersinia frederiksenii (ASBTYf) in a lipid environment, which reveal that a large rigid-body rotation of a substrate-binding domain gives the conserved 'crossover' region, where two discontinuous helices cross each other, alternating accessibility from either side of the cell membrane. This result has implications for the location and orientation of the bile acid during transport, as well as for the translocation pathway for Na+. [ABSTRACT FROM AUTHOR] |
| Copyright of Nature is the property of Springer Nature and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) | |
| Database: | Psychology and Behavioral Sciences Collection |
| FullText | Links: – Type: pdflink Text: Availability: 0 |
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| Header | DbId: pbh DbLabel: Psychology and Behavioral Sciences Collection An: 93923103 AccessLevel: 6 PubType: Academic Journal PubTypeId: academicJournal PreciseRelevancyScore: 0 |
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| Items | – Name: Title Label: Title Group: Ti Data: Structural basis of the alternating-access mechanism in a bile acid transporter. – Name: Author Label: Authors Group: Au Data: <searchLink fieldCode="AR" term="%22Zhou%2C+Xiaoming%22">Zhou, Xiaoming</searchLink><br /><searchLink fieldCode="AR" term="%22Levin%2C+Elena+J%2E%22">Levin, Elena J.</searchLink><br /><searchLink fieldCode="AR" term="%22Pan%2C+Yaping%22">Pan, Yaping</searchLink><br /><searchLink fieldCode="AR" term="%22McCoy%2C+Jason+G%2E%22">McCoy, Jason G.</searchLink><br /><searchLink fieldCode="AR" term="%22Sharma%2C+Ruchika%22">Sharma, Ruchika</searchLink><br /><searchLink fieldCode="AR" term="%22Kloss%2C+Brian%22">Kloss, Brian</searchLink><br /><searchLink fieldCode="AR" term="%22Bruni%2C+Renato%22">Bruni, Renato</searchLink><br /><searchLink fieldCode="AR" term="%22Quick%2C+Matthias%22">Quick, Matthias</searchLink><br /><searchLink fieldCode="AR" term="%22Zhou%2C+Ming%22">Zhou, Ming</searchLink> – Name: TitleSource Label: Source Group: Src Data: <searchLink fieldCode="JN" term="%22Nature%22">Nature</searchLink>. 1/23/2014, Vol. 505 Issue 7484, p569-573. 5p. – Name: Subject Label: Subjects Group: Su Data: <searchLink fieldCode="DE" term="%22Bile+acids%22">Bile acids</searchLink><br /><searchLink fieldCode="DE" term="%22Cholesterol%22">Cholesterol</searchLink><br /><searchLink fieldCode="DE" term="%22Liver+cells%22">Liver cells</searchLink><br /><searchLink fieldCode="DE" term="%22Secretion%22">Secretion</searchLink><br /><searchLink fieldCode="DE" term="%22Enterohepatic+circulation%22">Enterohepatic circulation</searchLink><br /><searchLink fieldCode="DE" term="%22Fat-soluble+vitamins%22">Fat-soluble vitamins</searchLink><br /><searchLink fieldCode="DE" term="%22Intestinal+physiology%22">Intestinal physiology</searchLink> – Name: Abstract Label: Abstract Group: Ab Data: Bile acids are synthesized from cholesterol in hepatocytes and secreted through the biliary tract into the small intestine, where they aid in absorption of lipids and fat-soluble vitamins. Through a process known as enterohepatic recirculation, more than 90% of secreted bile acids are then retrieved from the intestine and returned to the liver for resecretion. In humans, there are two Na+-dependent bile acid transporters involved in enterohepatic recirculation, the Na+-taurocholate co-transporting polypeptide (NTCP; also known as SLC10A1) expressed in hepatocytes, and the apical sodium-dependent bile acid transporter (ASBT; also known as SLC10A2) expressed on enterocytes in the terminal ileum. In recent years, ASBT has attracted much interest as a potential drug target for treatment of hypercholesterolaemia, because inhibition of ASBT reduces reabsorption of bile acids, thus increasing bile acid synthesis and consequently cholesterol consumption. However, a lack of three-dimensional structures of bile acid transporters hampers our ability to understand the molecular mechanisms of substrate selectivity and transport, and to interpret the wealth of existing functional data. The crystal structure of an ASBT homologue from Neisseria meningitidis (ASBTNM) in detergent was reported recently, showing the protein in an inward-open conformation bound to two Na+ and a taurocholic acid. However, the structural changes that bring bile acid and Na+ across the membrane are difficult to infer from a single structure. To understand the structural changes associated with the coupled transport of Na+ and bile acids, here we solved two structures of an ASBT homologue from Yersinia frederiksenii (ASBTYf) in a lipid environment, which reveal that a large rigid-body rotation of a substrate-binding domain gives the conserved 'crossover' region, where two discontinuous helices cross each other, alternating accessibility from either side of the cell membrane. This result has implications for the location and orientation of the bile acid during transport, as well as for the translocation pathway for Na+. [ABSTRACT FROM AUTHOR] – Name: AbstractSuppliedCopyright Label: Group: Ab Data: <i>Copyright of Nature is the property of Springer Nature and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.) |
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| RecordInfo | BibRecord: BibEntity: Identifiers: – Type: doi Value: 10.1038/nature12811 Languages: – Code: eng Text: English PhysicalDescription: Pagination: PageCount: 5 StartPage: 569 Subjects: – SubjectFull: Bile acids Type: general – SubjectFull: Cholesterol Type: general – SubjectFull: Liver cells Type: general – SubjectFull: Secretion Type: general – SubjectFull: Enterohepatic circulation Type: general – SubjectFull: Fat-soluble vitamins Type: general – SubjectFull: Intestinal physiology Type: general Titles: – TitleFull: Structural basis of the alternating-access mechanism in a bile acid transporter. Type: main BibRelationships: HasContributorRelationships: – PersonEntity: Name: NameFull: Zhou, Xiaoming – PersonEntity: Name: NameFull: Levin, Elena J. – PersonEntity: Name: NameFull: Pan, Yaping – PersonEntity: Name: NameFull: McCoy, Jason G. – PersonEntity: Name: NameFull: Sharma, Ruchika – PersonEntity: Name: NameFull: Kloss, Brian – PersonEntity: Name: NameFull: Bruni, Renato – PersonEntity: Name: NameFull: Quick, Matthias – PersonEntity: Name: NameFull: Zhou, Ming IsPartOfRelationships: – BibEntity: Dates: – D: 23 M: 01 Text: 1/23/2014 Type: published Y: 2014 Identifiers: – Type: issn-print Value: 00280836 Numbering: – Type: volume Value: 505 – Type: issue Value: 7484 Titles: – TitleFull: Nature Type: main |
| ResultId | 1 |
