Journal Article

Activation of polycystin-1 signaling by binding of stalk-derived peptide agonists

Pawnikar, Shristi, Magenheimer, Brenda S, Joshi, Keya, Haldane, Allan, Miao, Yinglong, Maser, Robin L, Nevarez-Munoz, Ericka

2024

Overview

Polycystin-1 (PC1) is the protein product of the PKD1 gene whose mutation causes autosomal dominant Polycystic Kidney Disease (ADPKD). PC1 is an atypical G protein-coupled receptor (GPCR) with an autocatalytic GAIN domain that cleaves PC1 into extracellular N-terminal and membrane-embedded C-terminal (CTF) fragments. Recently, activation of PC1 CTF signaling was shown to be regulated by a stalk tethered agonist (TA), resembling the mechanism observed for adhesion GPCRs. Here, synthetic peptides of the first 9- (p9), 17- (p17), and 21-residues (p21) of the PC1 stalk TA were shown to re-activate signaling by a stalkless CTF mutant in human cell culture assays. Novel Peptide Gaussian accelerated molecular dynamics (Pep-GaMD) simulations elucidated binding conformations of p9, p17, and p21 and revealed multiple specific binding regions to the stalkless CTF. Peptide agonists binding to the TOP domain of PC1 induced close TOP-putative pore loop interactions, a characteristic feature of stalk TA-mediated PC1 CTF activation. Additional sequence coevolution analyses showed the peptide binding regions were consistent with covarying residue pairs identified between the TOP domain and the stalk TA. These insights into the structural dynamic mechanism of PC1 activation by TA peptide agonists provide an in-depth understanding that will facilitate the development of therapeutics targeting PC1 for ADPKD treatment.

• Publisher: eLife Sciences Publications Ltd,eLife Sciences Publications, Ltd
• Subject: ADPKD / Agonists / Cell culture / Coevolution / Cyclin-dependent kinase inhibitor p21 / Drug development / Experiments / G protein-coupled receptors / Humans / Kidney diseases / Molecular Dynamics Simulation / PC1 / Peptides / Peptides - chemistry / Peptides - metabolism / Peptides - pharmacology / Polycystic kidney / Polycystic kidney disease 1 protein / Polycystic Kidney, Autosomal Dominant - drug therapy / Polycystic Kidney, Autosomal Dominant - genetics / Polycystic Kidney, Autosomal Dominant - metabolism / Protein Binding / Protein Conformation / Proteins / Signal Transduction / Simulation / stalk-derived peptide agonists / Structural Biology and Molecular Biophysics / Synthetic peptides / TRPP Cation Channels - chemistry / TRPP Cation Channels - genetics / TRPP Cation Channels - metabolism