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This Article Full Text Full Text (PDF) Supplemental Material All Versions of this Article: 297/5/F1310    most recent 00412.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Casuscelli, J. Articles by Boggon, T. J. PubMed PubMed Citation Articles by Casuscelli, J. Articles by Boggon, T. J.

Analysis of the cytoplasmic interaction between polycystin-1 and polycystin-2

Jozefina Casuscelli,^1,* Stefan Schmidt,^1,* Brenda DeGray,¹ Edward T. Petri,¹ Andjelka eli,¹ Ewa Folta-Stogniew,³ Barbara E. Ehrlich,^1,4 and Titus J. Boggon¹

Departments of ¹Pharmacology and ; ⁴Cellular and Molecular Physiology and ; ³W. M. Keck Foundation Biotechnology Resource Laboratory, Yale University School of Medicine, New Haven, Connecticut

Submitted July 22, 2009 ; accepted in final form September 2, 2009

Autosomal dominant polycystic kidney disease (ADPKD) arises following mutations of either Pkd1 or Pkd2. The proteins these genes encode, polycystin-1 (PC1) and polycystin-2 (PC2), form a signaling complex using direct intermolecular interactions. Two distinct domains in the C-terminal tail of PC2 have recently been identified, an EF-hand and a coiled-coil domain. Here, we show that the PC2 coiled-coil domain interacts with the C-terminal tail of PC1, but that the PC2 EF-hand domain does not. We measured the K_0.5 of the interaction between the C-terminal tails of PC1 and PC2 and showed that the direct interaction of these proteins is abrogated by a PC1 point mutation that was identified in ADPKD patients. Finally, we showed that overexpression of the PC1 C-terminal tail in MDCK cells alters the Ca²⁺ response, but that overexpression of the PC1 C-terminal tail containing the disease mutation does not. These results allow a more detailed understanding of the mechanism of pathogenic mutations in the cytoplasmic regions of PC1 and PC2.

polycystic kidney disease; calcium signaling; surface plasmon resonance; EF-hand; coiled-coil domain