Among the thirteen human aquaporins (AQP0-AQP12) distributed within cells of the stomach, duodenum, pancreas, airways, lungs, salivary glands, sweat glands, eyes, lacrimal glands, and the inner ear, AQP5 has been implicated in Sjogren's disease and in cancers of the lung, pancreas, colon etc.. Defective trafficking of AQP5 was found responsible for Sjogren's disease which inflicts about 4 million people (mostly women) in the US. Overexpression of AQP5 was identified in promoting cell proliferation and inhibiting apoptosis. Meanwhile, high-resolution x-ray structure of AQP5 has recently been determined. AQP5 resembles other aquaporins in its tetrameric conformation and in its water pore structure formed by each protomer. However, it lacks the four-fold quasi-symmetry among its four protomers and it contains a lipid, PS6, in its central pore. In light of the existent in vtro studies of AQP5's functions and its crystal structure, the following questions stand out: How does the structure of AQP5 embedded in the cell membrane under physiological conditions deviate from its crystallographic form? Does PS6 gate or inhibit the central pore? What are the specificities of the lipid-AQP5 interaction? How does the protein respond to its environmental changes in pH? And how does it respond to chemical modifications to its residues? These questions on the structure-function correlations of AQP5 need to be answered before new drugs can be designed that specifically target this protein. Answering these questions requires conducting extensive in silico experiments in an innovated approach. Two all-atom model systems of AQP5 embedded in a patch of lipid bi- layer explicitly solvated in physiological saline will be investigated: One with PS6 in the central pore of AQP5 and one without.
Three specific aims will be pursued: 1.Determine the roles of the lipid in the central pore and identify the mechanism of its gating or inhibiting action. 2. Identify the protein's mechanisms of biological functions and determine its response to environmental changes. 3. Quantify AQP5's response to chemical modifications and thus identify the mechanisms of signaling, gating, or inhibiting its physiological functions. Upon completion of the proposed research, a detailed understanding will be achieved about AQP5's structure- function correlations: AQP5's degree of accessibility for trafficking before and after phosphorylation at the selected sites, the affinity and specificit of binding a lipid in its central pore, and the mechanisms of inhibiting and gating its physiological functions. The knowledge so gained will positively impact on finding new medicines to prevent and control AQP5-related diseases.

Public Health Relevance

Aquaporin V, a water channel protein in the cell membrane, has been found to be related to Sjogren's syndrome, which inflicts about four million people (mostly women) in the US, and to several forms of cancer including pancreatic and lung cancers. This proposed research aims to bridge the gap between two currently available sets of knowledge by establishing the structure-function correlations of Aquaporin V and mutants. This research will lead to new ways of designing drugs for cancers and Sjogren's that specifically target Aquaporin V.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Continuance Award (SC3)
Project #
2SC3GM084834-05
Application #
8414118
Study Section
Special Emphasis Panel (ZGM1-TWD-1 (SC))
Program Officer
Krasnewich, Donna M
Project Start
2008-08-01
Project End
2017-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2013
Total Cost
$110,250
Indirect Cost
$35,250
Name
University of Texas Health Science Center San Antonio
Department
Physics
Type
Schools of Arts and Sciences
DUNS #
800189185
City
San Antonio
State
TX
Country
United States
Zip Code
78249
Chen, Liao Y (2014) Does Plasmodium falciparum have an Achilles' heel? Malar Chemother Control Elimin 3:
Alsharif, Shada A; Chen, Liao Y; Tlahuice-Flores, Alfredo et al. (2014) Interaction between functionalized gold nanoparticles in physiological saline. Phys Chem Chem Phys 16:3909-13
Zhang, Y B; Chen, L Y (2013) In silico study of Aquaporin V: Effects and affinity of the central pore-occluding lipid. Biophys Chem 171:24-30
Chen, Liao Y (2013) Glycerol modulates water permeation through Escherichia coli aquaglyceroporin GlpF. Biochim Biophys Acta 1828:1786-93
Chen, Liao Y (2013) Glycerol inhibits water permeation through Plasmodium falciparum aquaglyceroporin. J Struct Biol 181:71-6
Zhang, Yubo; Cui, Yubao; Chen, L Y (2012) Mercury inhibits the L170C mutant of aquaporin Z by making waters clog the water channel. Biophys Chem 160:69-74
Hu, Guodong; Chen, Liao Y; Wang, Jihua (2012) Insights into the mechanisms of the selectivity filter of Escherichia coli aquaporin Z. J Mol Model 18:3731-41
Cui, Yubao; Bastien, David A (2012) Molecular dynamics simulations of PfAQP from the malarial parasite Plasmodium falciparum. Mol Med Report 5:1197-201
Cui, Yubao; Bastien, David A (2011) Water transport in human aquaporin-4: molecular dynamics (MD) simulations. Biochem Biophys Res Commun 412:654-9
Renthal, Robert; Brancaleon, Lorenzo; Pena, Isaac et al. (2011) Interaction of a two-transmembrane-helix peptide with lipid bilayers and dodecyl sulfate micelles. Biophys Chem 159:321-7

Showing the most recent 10 out of 17 publications