Mechanistic studies of the apical sodium-dependent bile acid transporter

Raphael Alhadeff, Assaf Ganoth*, Isaiah T. Arkin

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

In mammals, the apical sodium-dependent bile acid transporter (ASBT) is responsible for the reuptake of bile acid from the intestine, thus recycling bile acid that is secreted from the gallbladder, for the purpose of digestion. As bile acid is synthesized from cholesterol, ASBT inhibition could have important implications in regulation of cholesterol levels in the blood. We report on a simulation study of the recently resolved structures of the inward-facing ASBT from Neisseria meningitidis and from Yersinia frederiksenii, as well as of an ASBT variant from Yersinia frederiksenii suggested to be in the outward-facing conformation. Classical and steered atomistic simulations and comprehensive potential of mean force analyses of ASBT, both in the absence and presence of ions and substrate, allow us to characterize and gain structural insights into the Na+ binding sites and propose a mechanistic model for the transport cycle. In particular, we investigate structural features of the ion translocation pathway, and suggest a third putative Na+ binding site. Our study sheds light on the structure-function relationship of bacterial ASBT and may promote a deeper understanding of transport mechanism altogether.

Original languageAmerican English
Pages (from-to)1107-1117
Number of pages11
JournalProteins: Structure, Function and Bioinformatics
Volume83
Issue number6
DOIs
StatePublished - 1 Jun 2015

Bibliographical note

Publisher Copyright:
© 2015 Wiley Periodicals, Inc.

Keywords

  • Membrane protein
  • Molecular dynamics
  • Na-binding
  • Transport mechanism

Fingerprint

Dive into the research topics of 'Mechanistic studies of the apical sodium-dependent bile acid transporter'. Together they form a unique fingerprint.

Cite this