Human Molecular Genetics, 2000, Vol. 9, No. 11 1641-1649
© 2000 Oxford University Press
Strong homophilic interactions of the Ig-like domains of polycystin-1, the protein product of an autosomal dominant polycystic kidney disease gene, PKD1
Genzyme Corporation, 1 Mountain Road, Framingham, MA 01701-9322, USA
The 14 kb mRNA of the polycystic kidney disease gene PKD1 encodes a novel large (~460 kDa) protein, polycystin-1, of unknown function that is responsible for autosomal dominant polycystic kidney disease (ADPKD). The unique organization of multiple adhesive domains of polycystin-1, including 16 Ig-like domains (or PKD domains) suggests that it may play an important role in cell–cell/cell–matrix interactions. Here we demonstrate the localization of polycystin-1 to epithelial cell–cell contacts in culture. These results along with structural predictions prompted us to propose that polycystin-1 is involved in cell–cell adhesion through its cluster of Ig-like repeats. We show that Ig-like domains II–XVI are involved in strong calcium-independent homophilic interactions in vitro. Domains XI–XVI form interactions with high affinity (Kd = 60 nM) and domains II–V exhibit the lowest binding affinity (Kd = 730 nM) in these studies. Most importantly, we show that antibodies raised against Ig-like domains of polycystin-1 disrupt cell–cell interactions in MDCK cell monolayers, thus indicating that polycystin-1 is directly involved in the cell–cell adhesion process. Collectively, these data suggest that interactions of the Ig-like repeats of polycystin-1 play an important role in mediating intercellular adhesion. We suggest that the loss of these interactions due to mutations in polycystin-1 may be an important step in cystogenesis.
+ To whom correspondence should be addressed. Tel: +1 508 270 2134; Fax: +1 508 620 1203; Email: oxana.ibraghimov@genzyme.com
§ Deceased August 1999. This article is respectfully dedicated to his memory in recognition of his significant contribution to this study.
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