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Activation of Polycystin-1 Signaling by Binding of Stalk-derived Peptide Agonists by S. Pawnikar; B. S. Magenheimer; E. Nevarez-Munoz; A. Haldane; R. L. Maser; Y. Miao is a scholarly article available to read on EtoBox.

What is Activation of Polycystin-1 Signaling by Binding of Stalk-derived Peptide Agonists about?

Polycystin-1 (PC1) is the membrane protein product of the PKD1 gene whose mutation is responsible for 85% of the cases of autosomal dominant polycystic kidney disease (ADPKD). ADPKD is primarily characterized by the formation of renal cysts and potential kidney failure. PC1 is an atypical G protein-coupled receptor (GPCR) consisting of 11 transmembrane helices and an autocatalytic GAIN domain that cleaves PC1 into extracellular N-terminal (NTF) and membrane-embedded C-terminal (CTF) fragments. Recently, signaling activation of the PC1 CTF was shown to be regulated by a stalk tethered agonist (TA), a distinct mechanism observed in the adhesion GPCR family. A novel allosteric activation pathway was elucidated for the PC1 CTF through a combination of Gaussian accelerated molecular dynamics (GaMD), mutagenesis and cellular signaling experiments. Here, we show that synthetic, soluble peptides with 7 to 21 residues derived from the stalk TA, in particular, peptides including the first 9 residues (p9), 17 residues (p17) and 21 residues (p21) exhibited the ability to re-activate signaling by a stalkless PC1 CTF mutant in cellular assays. To reveal molecular mechanisms of stalk peptide-medi

Author

S. Pawnikar; B. S. Magenheimer; E. Nevarez-Munoz; A. Haldane; R. L. Maser; Y. Miao

Publisher

Cold Spring Harbor Laboratory

Published

2024

Language

EN