title: Structural and molecular basis of the assembly of the TRPP2/PKD1 complex.
abstract: 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.
authors: Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
authors: Yong
authors: Y
authors: Yu
authors: Maximilian H
authors: MH
authors: Ulbrich
authors: Ming-Hui
authors: MH
authors: Li
authors: Zafir
authors: Z
authors: Buraei
authors: Xing-Zhen
authors: XZ
authors: Chen
authors: Albert C M
authors: AC
authors: Ong
authors: Liang
authors: L
authors: Tong
authors: Ehud Y
authors: EY
authors: Isacoff
authors: Jian
authors: J
authors: Yang
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D003460:Crystallization; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D017422:Sequence Analysis, DNA; D050396:TRPP Cation Channels / Q000235:genetics* / Q000378:metabolism; D014981:Xenopus
chemical_list: D046912:Multiprotein Complexes; D050396:TRPP Cation Channels