Approximately 0.1% of the world population is affected by autosomal dominant polycystic kidney disease (ADPKD), which is one of the most common genetic diseases in humans. This disease is caused by mutations in two polycystin proteins, PKD1 and TRPP2. PKD1 is a plasma membrane receptor probably involved in cell-cell and cell-matrix interactions. TRPP2 is a Ca2+-permeable nonselective cation channel present in the endoplasmic reticulum as well as on the plasma membrane. In kidney cells, they form a cell surface complex that may function as a mechanosensitive Ca2+-conducting ion channel that can be regulated by fluid flow in the kidney tubule. The association of TRPP2 and PKD1 is mediated, at least in part, by a coiled coil domain in the cytoplasmic C terminus of both proteins. TRPP3, related to but distinct from TRPP2, also forms a Ca2+-permeable nonselective cation channel, and deletion of its gene in mice is linked to fatal kidney defects. Its cytoplasmic C terminus also contains a coiled coil domain. Recently, it has been found that TRPP3 associates with a PKD1-like protein named PKD1L3 to form the receptors for sour taste in the tongue. Our long-term objective is to understand the structural, molecular and cellular mechanisms of the function and regulation of polycystins. The immediate goal is to investigate the assembly and stoichiometry of the TRPP2/PKD1 and TRPP3/PKD1L3 complexes. We propose to solve the crystal structure of the putative coiled coil domain of both complexes, determine the subunit stoichiometry of both complexes in cells, investigate the importance of the coiled coil domain interaction in the assembly of both complexes and in the PKD1 regulation of TRPP2 activity and PKD1L3 regulation of TRPP3 activity. We also propose to test the hypothesis that PKD1 and PKD1L3 directly participate to form the channel pore in the TRPP2/PKD1 complex and the TRPP3/PKD1L3 complex, respectively. This research will enhance our understanding of the molecular basis of polycystin function.

Public Health Relevance

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common genetic diseases in humans and is caused by mutations of polycystin complexes in kidney cells. The goal of this research is to understand how these complexes are formed and how they function.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM085234-04
Application #
8266530
Study Section
Special Emphasis Panel (ZRG1-MDCN-F (02))
Program Officer
Nie, Zhongzhen
Project Start
2009-05-01
Project End
2013-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
4
Fiscal Year
2012
Total Cost
$322,963
Indirect Cost
$119,592
Name
Columbia University (N.Y.)
Department
Biology
Type
Other Domestic Higher Education
DUNS #
049179401
City
New York
State
NY
Country
United States
Zip Code
10027
Zhu, Jiang; Yu, Yong; Ulbrich, Maximilian H et al. (2011) Structural model of the TRPP2/PKD1 C-terminal coiled-coil complex produced by a combined computational and experimental approach. Proc Natl Acad Sci U S A 108:10133-8
Li, Minghui; Yu, Yong; Yang, Jian (2011) Structural biology of TRP channels. Adv Exp Med Biol 704:1-23
Yu, Yong; Ulbrich, Maximilian H; Li, Ming-Hui et al. (2009) Structural and molecular basis of the assembly of the TRPP2/PKD1 complex. Proc Natl Acad Sci U S A 106:11558-63