Structural mechanisms of the polycystic kidney disease proteins
EMSL Project ID
50851
Abstract
Polycystin-1 and polycystin-2 (also known as PKD1 and PKD2) are fundamental for normal development and functioning of the renal and cardiovascular systems. Mutations in either PKD1 or PKD2 genes cause a prevalent autosomal dominant polycystic kidney disease (ADPKD). PKD1 and PKD2 co-assemble into a receptor/ion channel complex at primary cilia where they fulfill essential sensory roles by responding to mechanical force of fluid shear and/or chemical stimuli. Our overarching goal is to determine structures of the PKD1/2 complex to understand how this complex is assembled, regulated by cellular factors, activated by ligand(s), and perturbed by pathogenic mutations. Recently, the architecture of the PKD1/2 transmembrane core has been determined, but it lacks all the soluble domains that are known to be essential for ligand recognition and to participate in interaction with various cellular modulators. For instance, the C-terminal segments of PKD1 and PKD2 contain coiled-coil domains that contribute to complex assembly, bear calmodulin and G protein binding sites, and undergo phosphorylation by protein kinase A and posttranslational hydroxylation at two proline residues. Of great concern, the current PKD1/2 complex structure represents a nonfunctional complex and thus is an inadequate model to understand normal function of the complex. We propose to solve structures of PKD1/2 complex with intact C-terminal domains, with the goal of understanding how these cytosolic domains associate with and allosterically regulate the transmembrane core. We also suspect that inclusion of cytosolic domains might help capture the PKD1/2 complex in a more physiologically relevant functional state.
Project Details
Start Date
2019-06-15
End Date
2019-10-15
Status
Closed
Released Data Link
Team
Principal Investigator
Team Members