title: A polycystin-2 (TRPP2) dimerization domain essential for the function of heteromeric polycystin complexes.
abstract: Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in two genes, PKD1 and PKD2, which encode polycystin-1 (PC1) and polycystin-2 (PC2), respectively. Earlier work has shown that PC1 and PC2 assemble into a polycystin complex implicated in kidney morphogenesis. PC2 also assembles into homomers of uncertain functional significance. However, little is known about the molecular mechanisms that direct polycystin complex assembly and specify its functions. We have identified a coiled coil in the C-terminus of PC2 that functions as a homodimerization domain essential for PC1 binding but not for its self-oligomerization. Dimerization-defective PC2 mutants were unable to reconstitute PC1/PC2 complexes either at the plasma membrane (PM) or at PM-endoplasmic reticulum (ER) junctions but could still function as ER Ca(2+)-release channels. Expression of dimerization-defective PC2 mutants in zebrafish resulted in a cystic phenotype but had lesser effects on organ laterality. We conclude that C-terminal dimerization of PC2 specifies the formation of polycystin complexes but not formation of ER-localized PC2 channels. Mutations that affect PC2 C-terminal homo- and heteromerization are the likely molecular basis of cyst formation in ADPKD.
authors.affiliation: Centre de Recherche en Neurophysiologie et Neurobiologie de Marseille, UMR 6231, CNRS, Université de la Méditerranée, Bd Pierre Dramard, Marseille Cedex 15, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Giamarchi
authors.forename: Shuang
authors.initials: S
authors.lastname: Feng
authors.forename: Lise
authors.initials: L
authors.lastname: Rodat-Despoix
authors.forename: Yaoxian
authors.initials: Y
authors.lastname: Xu
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Bubenshchikova
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Newby
authors.forename: Jizhe
authors.initials: J
authors.lastname: Hao
authors.forename: Christelle
authors.initials: C
authors.lastname: Gaudioso
authors.forename: Marcel
authors.initials: M
authors.lastname: Crest
authors.forename: Andrei N
authors.initials: AN
authors.lastname: Lupas
authors.forename: Eric
authors.initials: E
authors.lastname: Honoré
authors.forename: Michael P
authors.initials: MP
authors.lastname: Williamson
authors.forename: Tomoko
authors.initials: T
authors.lastname: Obara
authors.forename: Albert C M
authors.initials: AC
authors.lastname: Ong
authors.forename: Patrick
authors.initials: P
authors.lastname: Delmas
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D019281:Dimerization; D004721:Endoplasmic Reticulum / Q000378:metabolism / Q000648:ultrastructure; D015870:Gene Expression; D006801:Humans; D007668:Kidney / Q000473:pathology; D008969:Molecular Sequence Data; D009154:Mutation; D016891:Polycystic Kidney, Autosomal Dominant / Q000235:genetics*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D050396:TRPP Cation Channels / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D020798:Two-Hybrid System Techniques; D015027:Zebrafish / Q000235:genetics
chemical_list: D002118:Calcium; D050396:TRPP Cation Channels