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

被引:142
作者
Ibraghimov-Beskrovnaya, O [1 ]
Bukanov, NO [1 ]
Donohue, LC [1 ]
Dackowski, WR [1 ]
Klinger, KW [1 ]
Landes, GM [1 ]
机构
[1] Genzyme Corp, Framingham, MA 01701 USA
关键词
D O I
10.1093/hmg/9.11.1641
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The 14 kb mRNA of the polycystic kidney disease gene PKD1 encodes a novel large (similar to 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 (K-d = 60 nM) and domains II-V exhibit the lowest binding affinity (K-d = 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.
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页码:1641 / 1649
页数:9
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