PKD1 interacts with PKD2 through a probable coiled-coil domain
Feng Qian1, F. Joseph Germino2, Yiqiang Cai3, Xiangbin Zhang1, Stefan Somlo3
& Gregory G. Germino1, 4
1Department of Medicine, Division of Nephrology/Ross970, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
2Department of Medicine, University of Medicine and Dentistry of New Jersey, Member CINJ, New Brunswick, New Jersey 08901, USA.
3Departments of Medicine and Molecular Genetics, Division of Nephrology, Albert Einstein College of Medicine, Bronx, New Yorkl 0461, USA.
4e-mail: ggermino@welchlink.welch.jhu.edu
Autosomal dominant polycystic kidney disease (ADPKD) describes a group of at least three genetically distinct disorders with almost identical clinical features1−6 that collectively affects 1:1,000 of the population7. Affected individuals typically develop large cystic kidneys and approximately one half develop end-stage renal disease by their seventh decade. It has been suggested that the diseases result from defects in interactive factors involved in a common pathway. The recent discovery of the genes for the two most common forms of ADPKD has provided an opportunity to test this hypothesis5,6,8−10. We describe a previously unrecognized coiled-coil domain within the C terminus of the PKD1 gene product, polycystin, and demonstrate that it binds specifically to the C terminus of PKD2. Homotypic interactions involving the C terminus of each are also demonstrated. We show that naturally occurring pathogenic mutations of PKD1 and PKD2 disrupt their associations. We have characterized the structural basis of their heterotypic interactions by deletional and site-specific mutagenesis. Our data suggest that PKD1 and PKD2 associate physically in vivo and may be partners of a common signalling cascade involved in tubular morphogenesis.
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