Strong homophilic interactions of the Ig-like domains of polycystin-1,the protein product of an autosomal dominant polycystic kidney disease gene, PKD1

The 14 kb mRNA of the polycystic kidney disease gene PKD1 encodes a novel l arge (similar to 460 kDa) protein, polycystin-1, of unknown function that i s responsible for autosomal dominant polycystic kidney disease (ADPKD), The unique organization of multiple adhesive domains of polycystin-1, includin g 16 Ig-like domains (or PKD domains) suggests that it may play an importan t role in cell-cell/cell-matrix interactions. Here we demonstrate the local ization of polycystin-1 to epithelial cell-cell contacts in culture. These results along with structural predictions prompted us to propose that polyc ystin-1 is involved in cell-cell adhesion through its cluster of Ig-like re peats, We show that Ig-like domains II-XVI are involved in strong calcium-i ndependent homophilic interactions in vitro. Domains XI-XVI form interactio ns with high affinity (K-d = 60 nM) and domains II-V exhibit the lowest bin ding affinity (K-d = 730 nM) in these studies, Most importantly, we show th at antibodies raised against Ig-like domains of polycystin-1 disrupt cell-c ell interactions in MDCK cell monolayers, thus indicating that polycystin-1 is directly involved in the cell-cell adhesion process. Collectively, thes e data suggest that interactions of the ig-like repeats of polycystin-1 pla y an important role in mediating intercellular adhesion. We suggest that th e loss of these interactions due to mutations in polycystin-1 may be an imp ortant step in cystogenesis.