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Structure and permeation mechanism of a mammalian urea transporter

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Details

Original languageEnglish
Pages (from-to)11194-11199
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number28
DOIs
Publication statusPublished - 10 Jul 2012
Publication typeA1 Journal article-refereed

Abstract

As an adaptation to infrequent access to water, terrestrial mammals produce urine that is hyperosmotic to plasma. To prevent osmotic diuresis by the large quantity of urea generated by protein catabolism, the kidney epithelia contain facilitative urea transporters (UTs) that allow rapid equilibration between the urinary space and the hyperosmotic interstitium. Here we report the first X-ray crystal structure of a mammalian UT, UT-B, at a resolution of 2.36 Å. UT-B is a homotrimer and each protomer contains a urea conduction pore with a narrow selectivity filter. Structural analyses and molecular dynamics simulations showed that the selectivity filter has two urea binding sites separated by an approximately 5.0 kcal/mol energy barrier. Functional studies showed that the rate of urea conduction in UT-B is increased by hypoosmotic stress, and that the site of osmoregulation coincides with the location of the energy barrier.

ASJC Scopus subject areas

Keywords

  • Channels, Membrane proteins, Osmosensing, Renal physiology