STRUCTURAL BIOLOGY OF POLYCYSTINS

Massachusetts General Hospital, Boston MA

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Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is a relatively common genetic disorder that leads to renal failure in adult life. Two of the responsible chromosomal loci, PKD1 and PKD2, have been mapped and their gene products characterized. PKD1 and PKD2 appear to participate in a common signaling pathway that directs tubular morphogenesis. Unfortunately, little is current known regarding the structural basis of polycystin function. The PKD1 gene transcript encodes a 4304 amino acid protein (polycystin-1) that appears to mediate adhesive protein-protein and protein-carbohydrate interactions in the extracellular compartment. Modeling, based on sequence homology, suggests that the amino-terminal half of polycystin-1 is extracellular and contains leucine-rich repeats, LDL-A and C-type lectins, and multiple copies of a noel 80 amino acid domain. The remaining protein is divided into 7 or 11 transmembrane domains and a 225 amino acid cytoplasmic tail. The PKD2 gene transcript, in contrast, encodes a protein of only 968 amino acids (polycystin-2) that is thought to form an ion channel or pore with cytoplasmic amino and carboxy termini. The extracellular events sensed by PKD1 may regulate PKD2 channel activity through interactions between their carboxyl-terminal cytoplasmic domains. The specific goal of this proposal is to understand the molecular basis for polycystin function at the atomic level. Eventually, the crystallography will be expanded to include complexes of these key regulatory molecules with specific cytoplasmic and extracellular effectors. This project should provide a solid structural context for interpreting the emerging molecular biology of ADPKD while suggesting new possibilities for meaningful clinical intervention.