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Cited by 9Receptor Mechanisms and SignalingGenetic and Kidney Cyst DiseasesProtein Kinase Regulation and GTPase Signaling

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

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Pawnikar, Shristi, Magenheimer, Brenda S, Joshi, Keya, Nevarez-Munoz, Ericka, Haldane, Allan, Maser, Robin L, Miao, Yinglong·2024·eLife
DOI 10.7554/elife.95992PMC PMC11458180

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Abstract

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.

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Research works printed but not linked: 68

  1. Aoto, 2016, NMR characterization of information flow and allosteric communities in the MAP Kinase p38γ, Scientific Reports, 6, 10.1038/srep28655 · DOI
  2. Araç, 2012, A novel evolutionarily conserved domain of cell-adhesion GPCRs mediates autoproteolysis, The EMBO Journal, 31, 1364, 10.1038/emboj.2012.26 · DOI
  3. Bhattarai, 2020, G-protein-coupled receptor-membrane interactions depend on the receptor activation state, Journal of Computational Chemistry, 41, 460, 10.1002/jcc.26082 · DOI
  4. Cai, 2014, Altered trafficking and stability of polycystins underlie Polycystic Kidney Disease, The Journal of Clinical Investigation, 124, 5129, 10.1172/JCI67273 · DOI
  5. Chuang, 2018, A molecular dynamics simulation study decodes the Zika virus NS5 methyltransferase bound to SAH and RNA analogue, Scientific Reports, 8, 10.1038/s41598-018-24775-4 · DOI
  6. Dalagiorgou, 2013, Mechanical stimulation of polycystin-1 induces human osteoblastic gene expression via potentiation of the calcineurin/NFAT signaling axis, Cellular and Molecular Life Sciences, 70, 167, 10.1007/s00018-012-1164-5 · DOI
  7. Darden, 1993, Particle mesh Ewald: An N⋅ log (N) method for Ewald sums in large systems, The Journal of Chemical Physics, 98, 10089, 10.1063/1.464397 · DOI
  8. Demberg, 2015, Identification of the tethered peptide agonist of the adhesion G protein-coupled receptor GPR64/ADGRG2, Biochemical and Biophysical Research Communications, 464, 743, 10.1016/j.bbrc.2015.07.020 · DOI
  9. Gilson, 1988, Calculation of the total electrostatic energy of a macromolecular system: solvation energies, binding energies, and conformational analysis, Proteins, 4, 7, 10.1002/prot.340040104 · DOI
  10. Haldane, 2019, Influence of multiple-sequence-alignment depth on potts statistical models of protein covariation, Physical Review. E, 99, 10.1103/PhysRevE.99.032405 · DOI
  11. Haldane, 2021, Mi3-GPU: MCMC-based Inverse Ising Inference on GPUs for protein covariation analysis, Computer Physics Communications, 260, 10.1016/j.cpc.2020.107312 · DOI
  12. Harris, 2014, Genetic mechanisms and signaling pathways in autosomal dominant Polycystic Kidney Disease, The Journal of Clinical Investigation, 124, 2315, 10.1172/JCI72272 · DOI
  13. Heyer, 2016, Predicted mutation strength of nontruncating pkd1 mutations aids genotype-phenotype correlations in autosomal dominant Polycystic Kidney Disease, Journal of the American Society of Nephrology, 27, 2872, 10.1681/ASN.2015050583 · DOI
  14. Hofherr, 2016, Targeted rescue of a Polycystic Kidney Disease mutation by lysosomal inhibition, Kidney International, 89, 949, 10.1016/j.kint.2015.11.015 · DOI
  15. Hopp, 2012, Functional polycystin-1 dosage governs autosomal dominant Polycystic Kidney Disease severity, The Journal of Clinical Investigation, 122, 4257, 10.1172/JCI64313 · DOI · Paper page
  16. Howe, 2021, Ensembl 2021, Nucleic Acids Research, 49, D884, 10.1093/nar/gkaa942 · DOI
  17. Humphrey, 1996, VMD: visual molecular dynamics, Journal of Molecular Graphics, 14, 33, 10.1016/0263-7855(96)00018-5 · DOI · Paper page
  18. Ibraghimov-Beskrovnaya, 2000, Strong homophilic interactions of the Ig-like domains of polycystin-1, the protein product of an autosomal dominant Polycystic Kidney Disease gene, PKD1, Human Molecular Genetics, 9, 1641, 10.1093/hmg/9.11.1641 · DOI
  19. Ingelfinger, 2017, Tolvaptan and autosomal dominant Polycystic Kidney Disease, New England Journal of Medicine, 377, 1988, 10.1056/NEJMe1714276 · DOI
  20. Kim, 2016, The polycystin complex mediates Wnt/Ca2+ signalling, Nature Cell Biology, 18, 752, 10.1038/ncb3363 · DOI
  21. Krappitz, 2016, Is it time to fold the cysts away?, Trends in Molecular Medicine, 22, 997, 10.1016/j.molmed.2016.10.001 · DOI
  22. Kurbegovic, 2014, Novel functional complexity of polycystin-1 by GPS cleavage in vivo: role in Polycystic Kidney Disease, Molecular and Cellular Biology, 34, 3341, 10.1128/MCB.00687-14 · DOI
  23. Lakhia, 2022, PKD1 and PKD2 mRNA cis-inhibition drives Polycystic Kidney Disease progression, Nature Communications, 13, 10.1038/s41467-022-32543-2 · DOI
  24. Levy, 2017, Potts Hamiltonian models of protein co-variation, free energy landscapes, and evolutionary fitness, Current Opinion in Structural Biology, 43, 55, 10.1016/j.sbi.2016.11.004 · DOI
  25. Liao, 2019, In silico studies of conformational dynamics of Mu opioid receptor performed using gaussian accelerated molecular dynamics, Journal of Biomolecular Structure & Dynamics, 37, 166, 10.1080/07391102.2017.1422025 · DOI
  26. Liebscher, 2014, A tethered agonist within the ectodomain activates the adhesion g protein-coupled receptors GPR126 and GPR133, Cell Reports, 9, 2018, 10.1016/j.celrep.2014.11.036 · DOI
  27. Magenheimer, 2021, Constitutive Signaling by the C-Terminal Fragment of polycystin-1 Is Mediated by a Tethered Peptide Agonist, 10.1101/2021.08.20.457171 · DOI
  28. Maser, 2003, Transient transfection assays for analysis of signal transduction in renal cells, Renal Disease: Techniques and Protocols, 1, 205, 10.1385/1-59259-392-5:205 · DOI
  29. Maser, 2020, Adhesion GPCRs as a paradigm for understanding polycystin-1 G protein regulation, Cellular Signalling, 72, 10.1016/j.cellsig.2020.109637 · DOI
  30. Maser, 2022, The GPCR properties of polycystin-1- A new paradigm, Frontiers in Molecular Biosciences, 9, 10.3389/fmolb.2022.1035507 · DOI
  31. Miao, 2014, Improved reweighting of accelerated molecular dynamics simulations for free energy calculation, Journal of Chemical Theory and Computation, 10, 2677, 10.1021/ct500090q · DOI
  32. Miao, 2015, Gaussian accelerated molecular dynamics: unconstrained enhanced sampling and free energy calculation, Journal of Chemical Theory and Computation, 11, 3584, 10.1021/acs.jctc.5b00436 · DOI
  33. Miao, 2016, Graded activation and free energy landscapes of a muscarinic G-protein–coupled receptor, PNAS, 113, 12162, 10.1073/pnas.1614538113 · DOI
  34. Miao, 2017, Gaussian accelerated molecular dynamics: theory, implementation, and applications, Annual Reports in Computational Chemistry, 13, 231, 10.1016/bs.arcc.2017.06.005 · DOI
  35. Miao, 2018, Structural basis for binding of allosteric drug leads in the adenosine a1 receptor, Scientific Reports, 8, 10.1038/s41598-018-35266-x · DOI
  36. Miao, 2018, Mechanism of the G-protein mimetic nanobody binding to a muscarinic G-protein-coupled receptor, PNAS, 115, 3036, 10.1073/pnas.1800756115 · DOI
  37. Nims, 2003, Transmembrane domain analysis of polycystin-1, the product of the Polycystic Kidney Disease-1 (PKD1) gene: evidence for 11 membrane-spanning domains, Biochemistry, 42, 13035, 10.1021/bi035074c · DOI
  38. Palermo, 2017, CRISPR-Cas9 conformational activation as elucidated from enhanced molecular simulations, PNAS, 114, 7260, 10.1073/pnas.1707645114 · DOI
  39. Pang, 2017, Gaussian accelerated molecular dynamics in NAMD, Journal of Chemical Theory and Computation, 13, 9, 10.1021/acs.jctc.6b00931 · DOI
  40. Park, 2018, Structural basis for arginine glycosylation of host substrates by bacterial effector proteins, Nature Communications, 9, 10.1038/s41467-018-06680-6 · DOI
  41. Pavel, 2014, Analysis of the cell surface expression of cytokine receptors using the surface protein biotinylation method, Cytokine Bioassays: Methods and Protocols, 1, 185, 10.1007/978-1-4939-0928-5_16 · DOI
  42. Pawnikar, 2020, Pathway and mechanism of drug binding to chemokine receptors revealed by accelerated molecular simulations, Future Medicinal Chemistry, 12, 1213, 10.4155/fmc-2020-0044 · DOI
  43. Pawnikar, 2022, Mechanism of tethered agonist-mediated signaling by polycystin-1, PNAS, 119, 10.1073/pnas.2113786119 · DOI
  44. Puri, 2004, Polycystin-1 activates the calcineurin/nfat (nuclear factor of activated t-cells) signaling pathway, Journal of Biological Chemistry, 279, 55455, 10.1074/jbc.M402905200 · DOI
  45. Qian, 2002, Cleavage of polycystin-1 requires the receptor for egg jelly domain and is disrupted by human autosomal-dominant Polycystic Kidney Disease 1-associated mutations, PNAS, 99, 16981, 10.1073/pnas.252484899 · DOI
  46. Rastelli, 2010, Fast and accurate predictions of binding free energies using MM-PBSA and MM-GBSA, Journal of Computational Chemistry, 31, 797, 10.1002/jcc.21372 · DOI
  47. Ricci, 2019, Deciphering off-target effects in crispr-cas9 through accelerated molecular dynamics, ACS Central Science, 5, 651, 10.1021/acscentsci.9b00020 · DOI
  48. Roe, 2013, PTRAJ and CPPTRAJ: software for processing and analysis of molecular dynamics trajectory data, Journal of Chemical Theory and Computation, 9, 3084, 10.1021/ct400341p · DOI
  49. Rossetti, 2009, Incompletely penetrant PKD1 alleles suggest a role for gene dosage in cyst initiation in Polycystic Kidney Disease, Kidney International, 75, 848, 10.1038/ki.2008.686 · DOI
  50. Sandford, 1997, Comparative analysis of the Polycystic Kidney Disease 1 (PKD1) gene reveals an integral membrane glycoprotein with multiple evolutionary conserved domains, Human Molecular Genetics, 6, 1483, 10.1093/hmg/6.9.1483 · DOI
  51. Schöneberg, 2015, Tethered agonists: a new mechanism underlying adhesion G protein-coupled receptor activation, Journal of Receptor and Signal Transduction Research, 35, 220, 10.3109/10799893.2015.1072978 · DOI
  52. Sibener, 2018, Isolation and visualization of a structural trigger that uncouples TCR signaling from pMHC binding, Cell, 174, 10.1016/j.cell.2018.06.017 · DOI
  53. Srinivasan, 1998, Continuum solvent studies of the stability of DNA, RNA, and Phosphoramidate−DNA helices, Journal of the American Chemical Society, 120, 9401, 10.1021/ja981844+ · DOI
  54. Stoveken, 2015, Adhesion G protein-coupled receptors are activated by exposure of a cryptic tethered agonist, PNAS, 112, 6194, 10.1073/pnas.1421785112 · DOI
  55. Su, 2018, Structure of the human PKD1-PKD2 complex, Science, 361, 10.1126/science.aat9819 · DOI · Paper page
  56. Sutters, 2001, Polycystin-1 transforms the cAMP growth-responsive phenotype of M-1 cells, Kidney International, 60, 484, 10.1046/j.1523-1755.2001.060002484.x · DOI
  57. Tan, 2011, Autosomal dominant Polycystic Kidney Disease: Genetics, mutations and microRNAs, Biochimica et Biophysica Acta, 1812, 1202, 10.1016/j.bbadis.2011.03.002 · DOI
  58. Valdés-Tresanco, 2021, gmx_MMPBSA: A new tool to perform end-state free energy calculations with GROMACS, Journal of Chemical Theory and Computation, 17, 6281, 10.1021/acs.jctc.1c00645 · DOI
  59. Vanommeslaeghe, 2015, CHARMM additive and polarizable force fields for biophysics and computer-aided drug design, Biochimica et Biophysica Acta, 1850, 861, 10.1016/j.bbagen.2014.08.004 · DOI
  60. Wang, 2006, Recent advances in free energy calculations with a combination of molecular mechanics and continuum models, Current Computer Aided-Drug Design, 2, 287, 10.2174/157340906778226454 · DOI
  61. Wang, 2017, Understanding the molecular basis of agonist/antagonist mechanism of human mu opioid receptor through gaussian accelerated molecular dynamics method, Scientific Reports, 7, 10.1038/s41598-017-08224-2 · DOI
  62. Wang, 2019, End-point binding free energy calculation with mm/pbsa and mm/gbsa: strategies and applications in drug design, Chemical Reviews, 119, 9478, 10.1021/acs.chemrev.9b00055 · DOI
  63. Wang, 2020, Peptide Gaussian accelerated molecular dynamics (Pep-GaMD): Enhanced sampling and free energy and kinetics calculations of peptide binding, The Journal of Chemical Physics, 153, 10.1063/5.0021399 · DOI
  64. Weston, 2001, The polycystin-1 C-type lectin domain binds carbohydrate in a calcium-dependent manner, and interacts with extracellular matrix proteins in vitro, Biochimica et Biophysica Acta, 1536, 161, 10.1016/S0925-4439(01)00046-1 · DOI
  65. Weston, 2003, Structure–function relationships of the extracellular domain of the autosomal Dominant Polycystic Kidney Disease‐associated protein, polycystin‐1, FEBS Letters, 538, 8, 10.1016/S0014-5793(03)00130-3 · DOI
  66. Xiao, 2022, Tethered peptide activation mechanism of the adhesion GPCRs ADGRG2 and ADGRG4, Nature, 604, 771, 10.1038/s41586-022-04590-8 · DOI
  67. Yu, 2007, Essential role of cleavage of polycystin-1 at G protein-coupled receptor proteolytic site for kidney tubular structure, PNAS, 104, 18688, 10.1073/pnas.0708217104 · DOI
  68. Zhou, 2018, HPEPDOCK: a web server for blind peptide–protein docking based on a hierarchical algorithm, Nucleic Acids Research, 46, W443, 10.1093/nar/gky357 · DOI

Metadata

Authors
Pawnikar, S., Magenheimer, B. S., Joshi, K., Nevarez-Munoz, E., Haldane, A., Maser, R. L., & Miao, Y.
Affiliations
  • University of North Carolina at Chapel Hill (US)
  • Clinical Laboratory Sciences, University of Kansas Medical Center
Corresponding author
Miao, Yinglong
ORCID
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2024-10-07
Volume
13
ISSN
2050-084X (ISSN-L)
DOI
10.7554/elife.95992
PMC
PMC11458180
OpenAlex
W4392374719
Cited by
9
References
1
Citations by year
2026: 4 · 2025: 5
Type
posted content
Language
en
Open access
Licence
Locations
  • eLife (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institutes of Health (R56DK135824, R01DK123590, R35-GM132090 and OD020095)
  • National Energy Research Scientific Computing Center (Project M2874)
  • Department of Defense Education Activity (CDMRP PRMRP Discovery Award (PR160710/W81XWH-17-1-0301))
  • Jared Grantham Kidney Institute, KU Medical Center (Pilot award 1004015)
  • University of North Carolina - Chapel Hill (Startup project 27110)
  • National Science Foundation (MRI1625061)
  • US Army Research Laboratory (W911NF-16-2-0189)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Kidney Cyst Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords
polycystin-1, autosomal dominant polycystic kidney disease, GAIN domain, C-terminal fragment, receptor activation mechanism, adhesion GPCRs
MeSH terms
Humans, Peptides, Protein Binding, Protein Conformation, Signal Transduction, Polycystic Kidney, Autosomal Dominant, TRPP Cation Channels, Molecular Dynamics Simulation

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