Aquaporins (AQPs) are critical for the active regulation of water balance required for normal cell function; defects in AQP water channels have been related to diseases such as nephrogenic diabetes insipidus. The structures of AQP1 together with that of glycerol facilitator, GIpF, have recently been determined to 2.2A, resolution by X-ray crystallographic methods. These structures have revealed the molecular mechanisms of ion, including proton, exclusion and the specific transport of water and glycerol across these channels. In dramatic contrast to all other known AQP water channels, AQP6 has been found to also facilitate the transport of negatively charged solutes (such as nitrate). AQP6 anion permeability is enhanced by the presence of Hg 2+ or by acidic pH. The activation of anion conductance upon Hg2+ binding is of great interest structurally as Hg2+ treatment has been shown in other aquaporins to abolish solute permeability including that for water. Recent studies have revealed that, even near neutral pH, AQP6 has a high selectivity for nitrate over CI, suggesting that the primary biological function of this aquaporin may not be water transport. The structural basis for the unique selectivity properties of AQP6 remains to be determined. To reveal the detailed mechanisms establishing the unique functional characteristics of AQP6, we propose to determine the structures of AQP6 with nitrate, Hg 2+, and at neutral and acidic pH, and conduct molecular dynamic simulations. These efforts, in turn, will provide a greater understanding of the general mechanisms regulating the transport of water and ions across water channels as well as through other ion channels. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM054132-09
Application #
6866809
Study Section
Special Emphasis Panel (ZRG1-BPC-B (02))
Program Officer
Deatherage, James F
Project Start
1996-05-01
Project End
2008-11-30
Budget Start
2004-12-01
Budget End
2005-11-30
Support Year
9
Fiscal Year
2005
Total Cost
$429,558
Indirect Cost
Name
Lawrence Berkeley National Laboratory
Department
Neurosciences
Type
Organized Research Units
DUNS #
078576738
City
Berkeley
State
CA
Country
United States
Zip Code
94720
Han, Bong-Gyoon; Guliaev, Anton B; Walian, Peter J et al. (2006) Water transport in AQP0 aquaporin: molecular dynamics studies. J Mol Biol 360:285-96
Li, H L; Sui, H X; Ghanshani, S et al. (1998) Two-dimensional crystallization and projection structure of KcsA potassium channel. J Mol Biol 282:211-6