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Abstract: PO1217

ADPKD Mutations in the Stalk/Tethered Agonist of Polycystin-1 CTF Affect Signaling and GPS Cleavage

Session Information

Category: Genetic Diseases of the Kidneys

  • 1001 Genetic Diseases of the Kidneys: Cystic


  • Maser, Robin L., University of Kansas Medical Center, Kansas City, Kansas, United States
  • Magenheimer, Brenda S., University of Kansas Medical Center, Kansas City, Kansas, United States
  • Nevarez Munoz, Ericka, University of Kansas Medical Center, Kansas City, Kansas, United States

Like Adhesion G protein-coupled receptors (aGPCRs), the N-terminal ectodomain of polycystin-1 (PC1) contains a membrane-proximal GAIN domain that catalyzes self-cleavage at its embedded GPCR proteolysis site (GPS), dividing these proteins into extracellular N-terminal (NTF) and membrane-embedded C-terminal (CTF) fragments. PC1 GPS cleavage is required for JAK/STAT signaling, PC1 maturation/trafficking and for prevention of renal cystogenesis in mice. ADPKD mutations that map within the GAIN domain inhibit GPS cleavage. We previously reported that the PC1 CTF utilizes an aGPCR-like tethered agonist mechanism to activate G-protein signaling to an NFAT reporter, which involves the short, N-terminal, extracellular stalk of the CTF serving as the tethered agonist. Deletion of the stalk dramatically inhibited signaling, while synthetic stalk-derived peptides could rescue signaling by the stalkless CTF and inhibit cystogenesis in metanephric organ cultures of hypomorphic Pkd1RC/RC kidneys. Here we assess the effect of stalk-localized ADPKD missense mutations on signaling by the dissociated CTF subunit and on GPS cleavage of full-length (FL) PC1 to gain additional insight for this regulatory mechanism.


Wild type (WT) or mutant, FL or CTF forms of PC1 were expressed in HEK293T cells and compared for activation of an NFAT promoter-luciferase reporter, levels of total and cell surface expression and GPS cleavage. Homology modeling of the PC1 GAIN domain was also performed.


Of 11 substitutions throughout the stalk, 6 significantly reduced, 2 increased, and 3 had no effect on signaling by PC1 CTF. Total and surface expression levels of the CTF mutants ranged from 62-125% of WT CTF. Most mutations had no effect on GPS cleavage of FL-PC1. Mutations that inhibited signaling or GPS cleavage mapped to the N-terminal portion of the stalk, while the 2 mutations that increased signaling were in the latter half.


PC1 stalk has more than one region important in regulation of CTF signaling- perhaps as part of the agonistic sequence or for its proper orientation. This study underscores the importance of PC1 GPS cleavage and suggests disruption of a tethered agonist mechanism may also contribute to renal cystogenesis. Better understanding of the tethered agonist mechanism is necessary for development of PKD1 mutation-specific therapies.


  • NIDDK Support