Open AccessStructural and molecular basis of the assembly of the TRPP2/PKD1 complex
Author(s) -
Yong Yu,
Maximilian H. Ulbrich,
Minghui Li,
Zafir Buraei,
Xing-Zhen Chen,
Albert Ong,
Liang Tong,
Ehud Y. Isacoff,
Jian Yang
Publication year - 2009
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.0903684106
Subject(s) - pkd1 , autosomal dominant polycystic kidney disease , coiled coil , trimer , protein subunit , microbiology and biotechnology , biology , chemistry , biophysics , biochemistry , genetics , kidney , gene , organic chemistry , dimer
Mutations in PKD1 and TRPP2 account for nearly all cases of autosomal dominant polycystic kidney disease (ADPKD). These 2 proteins form a receptor/ion channel complex on the cell surface. Using a combination of biochemistry, crystallography, and a single-molecule method to determine the subunit composition of proteins in the plasma membrane of live cells, we find that this complex contains 3 TRPP2 and 1 PKD1. A newly identified coiled-coil domain in the C terminus of TRPP2 is critical for the formation of this complex. This coiled-coil domain forms a homotrimer, in both solution and crystal structure, and binds to a single coiled-coil domain in the C terminus of PKD1. Mutations that disrupt the TRPP2 coiled-coil domain trimer abolish the assembly of both the full-length TRPP2 trimer and the TRPP2/PKD1 complex and diminish the surface expression of both proteins. These results have significant implications for the assembly, regulation, and function of the TRPP2/PKD1 complex and the pathogenic mechanism of some ADPKD-producing mutations.