Rational proteomics of PKD1. I. Modeling the three dimensional structure and ligand specificity of the C⋉ctin binding domain of Polycystin-1

Polycystin-1 (Pc-1) is the 4303 amino acid multi-domain glycoprotein product of the polycystic kidney disease-1 (PKD1) gene. Mutations in this gene are implicated in 85% of cases of human autosomal dominant polycystic disease. Although the biochemistry of Pc-1 has been extensively studied its three dimensional structure has yet to be determined. We are combining bioinformatics, computational and biochemical data to model the 3D structure and function of individual domains of Pc-1. A three dimensional model of the C-type lectin domain (CLD) of Pc-1 (sequence region 405-534) complexed with galactose (Gal) and a calcium ion (Ca⁺²) has been developed (the coordinates are available on request, e-mail: pletnevηwi.buffalo.edu). The model has α/β structural organization. It is composed of eight β strands and three α helices, and includes three disulfide bridges. It is consistent with the observed Ca⁺² dependence of sugar binding to CLD and identifies the amino acid side chains (E499, H501, E506, N518, T519 and D520) that are likely to bind the ligand. The model provides a reliable basis upon which to map functionally important residues using mutagenic experiments and to refine our knowledge about a preferred sugar ligand and the functional role of the CLD in polycystin-1.