title: Naturally occurring mutations alter the stability of polycystin-1 polycystic kidney disease (PKD) domains.
abstract: Mutations in polycystin-1 (PC1) can cause autosomal dominant polycystic kidney disease, which is a leading cause of renal failure. The available evidence suggests that PC1 acts as a mechanosensor, receiving signals from the primary cilia, neighboring cells, and extracellular matrix. PC1 is a large membrane protein that has a long N-terminal extracellular region (about 3000 amino acids) with a multimodular structure including 16 Ig-like polycystic kidney disease (PKD) domains, which are targeted by many naturally occurring missense mutations. Nothing is known about the effects of these mutations on the biophysical properties of PKD domains. Here we investigate the effects of several naturally occurring mutations on the mechanical stability of the first PKD domain of human PC1 (HuPKDd1). We found that several missense mutations alter the mechanical unfolding pathways of HuPKDd1, resulting in distinct mechanical phenotypes. Moreover, we found that these mutations also alter the thermodynamic stability of a structurally homologous archaeal PKD domain. Based on these findings, we hypothesize that missense mutations may cause autosomal dominant polycystic kidney disease by altering the stability of the PC1 ectodomain, thereby perturbing its ability to sense mechanical signals.
authors.affiliation: Department of Neuroscience and Cell Biology, MRC Centre for Protein Engineering, Lensfield Road, Cambridge CB2 1EW, United Kingdom.
authors.forename: Liang
authors.initials: L
authors.lastname: Ma
authors.forename: Meixiang
authors.initials: M
authors.lastname: Xu
authors.forename: Julia R
authors.initials: JR
authors.lastname: Forman
authors.forename: Jane
authors.initials: J
authors.lastname: Clarke
authors.forename: Andres F
authors.initials: AF
authors.lastname: Oberhauser
mesh_terms: D000595:Amino Acid Sequence; D001105:Archaea; D003001:Cloning, Molecular; D006801:Humans; D007700:Kinetics; D018625:Microscopy, Atomic Force / Q000379:methods; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D010641:Phenotype; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D050396:TRPP Cation Channels / Q000737:chemistry* / Q000378:metabolism; D013816:Thermodynamics
chemical_list: D050396:TRPP Cation Channels