Polycystin-2 activity is controlled by transcriptional coactivator with PDZ binding motif and PALS1-associated tight junction protein.

Duning K, Rosenbusch D, Schlüter MA, Tian Y, Kunzelmann K, Meyer N, Schulze U, Markoff A, Pavenstädt H, Weide T

Forschungsartikel (Zeitschrift)

Zusammenfassung

Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent monogenic cause of kidney failure, characterized by the development of renal cysts. ADPKD is caused by mutations of the polycystin-1 (PC1) or polycystin-2 (PC2) genes. PC2 encodes a Ca(2+)-permeable cation channel, and its dysfunction has been implicated in cyst development. The transcriptional coactivator with PDZ binding motif (TAZ) is required for the integrity of renal cilia. Its absence results in the development of renal cysts in a knock-out mouse model. TAZ directly interacts with PC2, and it has been suggested that another yet unidentified PDZ domain protein may be involved in the TAZ/PC2 interaction. Here we describe a novel interaction of TAZ with the multi-PDZ-containing PALS1-associated tight junction protein (PATJ). TAZ interacts with both the N-terminal PDZ domains 1-3 and the C-terminal PDZ domains 8-10 of PATJ, suggesting two distinct TAZ binding domains. We also show that the C terminus of PC2 strongly interacts with PDZ domains 8-10 and to a weaker extent with PDZ domains 1-3 of PATJ. Finally, we demonstrate that both TAZ and PATJ impair PC2 channel activity when co-expressed with PC2 in oocytes of Xenopus laevis. These results implicate TAZ and PATJ as novel regulatory elements of the PC2 channel and might thus be involved in ADPKD pathology.

Details zur Publikation

FachzeitschriftJournal of Biological Chemistry (J Biol Chem)
Jahrgang / Bandnr. / Volume285
Ausgabe / Heftnr. / Issue44
Seitenbereich33584-33588
StatusVeröffentlicht
Veröffentlichungsjahr2010
Sprache, in der die Publikation verfasst istEnglisch
DOI10.1074/jbc.C110.146381
StichwörterMice; Protein Structure Tertiary; Gene Expression Regulation; Nucleoside-Phosphate Kinase; Polycystic Kidney Diseases; Tight Junctions; Disease Models Animal; Xenopus laevis; TRPP Cation Channels; Oocytes; Animals; Humans; Transcriptional Activation; Protein Binding; Membrane Proteins; Mice; Protein Structure Tertiary; Gene Expression Regulation; Nucleoside-Phosphate Kinase; Polycystic Kidney Diseases; Tight Junctions; Disease Models Animal; Xenopus laevis; TRPP Cation Channels; Oocytes; Animals; Humans; Transcriptional Activation; Protein Binding; Membrane Proteins

Autor*innen der Universität Münster

Markov, Arseni
Klinik für Medizinische Genetik
Pavenstädt, Hermann-Joseph
Medizinische Klinik D (Med D)
Schulze, Ulf
Medizinische Klinik D (Med D)
Weide, Thomas
Medizinische Klinik D (Med D)