title: Specific association of the gene product of PKD2 with the TRPC1 channel.
abstract: The function(s) of the genes (PKD1 and PKD2) responsible for the majority of cases of autosomal dominant polycystic kidney disease is unknown. While PKD1 encodes a large integral membrane protein containing several structural motifs found in known proteins involved in cell-cell or cell-matrix interactions, PKD2 has homology to PKD1 and the major subunit of the voltage-activated Ca2+ channels. We now describe sequence homology between PKD2 and various members of the mammalian transient receptor potential channel (TRPC) proteins, thought to be activated by G protein-coupled receptor activation and/or depletion of internal Ca2+ stores. We show that PKD2 can directly associate with TRPC1 but not TRPC3 in transfected cells and in vitro. This association is mediated by two distinct domains in PKD2. One domain involves a minimal region of 73 amino acids in the C-terminal cytoplasmic tail of PKD2 shown previously to constitute an interacting domain with PKD1. However, distinct residues within this region mediate specific interactions with TRPC1 or PKD1. The C-terminal domain is sufficient but not necessary for the PKD2-TRPC1 association. A more N-terminal domain located within transmembrane segments S2 and S5, including a putative pore helical region between S5 and S6, is also responsible for the association. Given the ability of the TRPC to form functional homo- and heteromultimeric complexes, these data provide evidence that PKD2 may be functionally related to TRPC proteins and suggest a possible role of PKD2 in modulating Ca2+ entry in response to G protein-coupled receptor activation and/or store depletion.
authors: Renal Division, RW 563, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA.
authors: L
authors: L
authors: Tsiokas
authors: T
authors: T
authors: Arnould
authors: C
authors: C
authors: Zhu
authors: E
authors: E
authors: Kim
authors: G
authors: G
authors: Walz
authors: V P
authors: VP
authors: Sukhatme
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D015220:Calcium Channels; D002460:Cell Line; D006801:Humans; D007473:Ion Channels / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D007668:Kidney; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D008969:Molecular Sequence Data; D016891:Polycystic Kidney, Autosomal Dominant / Q000235:genetics*; D011506:Proteins / Q000737:chemistry; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D050052:TRPC Cation Channels; D050396:TRPP Cation Channels; D014162:Transfection
chemical_list: D015220:Calcium Channels; D007473:Ion Channels; D008565:Membrane Proteins; D011506:Proteins; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D050052:TRPC Cation Channels; D050396:TRPP Cation Channels; C096351:transient receptor potential cation channel, subfamily C, member 1