The structure of a PKD domain from polycystin-1: Implications for polycystic kidney disease

Most cases of autosomal dominant polycystic kidney disease (ADPKD) are the result of mutations in the PKD1 gene. The PKD1 gene codes for a large cell- surface glycoprotein, polycystin-1, of unknown function, which, based on it s predicted domain structure, may be involved in protein-protein and protei n-carbohydrate interactions. Approximately 30% of polycystin-1 consists of 16 copies of a novel protein module called the PKD domain. Here we show tha t this domain has a beta-sandwich fold, Although this fold is common to a n umber of cell-surface modules, the PKD domain represents a distinct protein family. The tenth PKD domain of human and Fugu polycystin-1 show extensive conservation of surface residues suggesting that this region could be a li gand-binding site. This structure will allow the likely effects of missense mutations in a large part of the PKD1 gene to be determined.