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Solution structure and characterization of the LGR8 receptor binding surface of insulin-like peptide 3.

Rosengren KJ, Zhang S, Lin F, Daly NL, Scott DJ, Hughes RA, Bathgate RA, Craik DJ, Wade JD
J Biol Chem 281 28287-95 (2006)
Cited: 37 times
EuropePMC logo PMID: 16867980

Abstract

Insulin-like peptide 3 (INSL3), a member of the relaxin peptide family, is produced in testicular Leydig cells and ovarian thecal cells. Gene knock-out experiments have identified a key biological role in initiating testes descent during fetal development. Additionally, INSL3 has an important function in mediating male and female germ cell function. These actions are elicited via its recently identified receptor, LGR8, a member of the leucine-rich repeat-containing G-protein-coupled receptor family. To identify the structural features that are responsible for the interaction of INSL3 with its receptor, its solution structure was determined by NMR spectroscopy together with in vitro assays of a series of B-chain alanine-substituted analogs. Synthetic human INSL3 was found to adopt a characteristic relaxin/insulin-like fold in solution but is a highly dynamic molecule. The four termini of this two-chain peptide are disordered, and additional conformational exchange is evident in the molecular core. Alanine-substituted analogs were used to identify the key residues of INSL3 that are responsible for the interaction with the ectodomain of LGR8. These include Arg(B16) and Val(B19), with His(B12) and Arg(B20) playing a secondary role, as evident from the synergistic effect on the activity in double and triple mutants involving these residues. Together, these amino acids combine with the previously identified critical residue, Trp(B27), to form the receptor binding surface. The current results provide clear direction for the design of novel specific agonists and antagonists of this receptor.

Reviews - 2h8b mentioned but not cited (2)

  1. Relaxin family peptides: structure-activity relationship studies. Patil NA, Rosengren KJ, Separovic F, Wade JD, Bathgate RAD, Hossain MA. Br J Pharmacol 174 950-961 (2017)
  2. Diverse functions of insulin-like 3 peptide. Esteban-Lopez M, Agoulnik AI. J Endocrinol 247 R1-R12 (2020)

Articles - 2h8b mentioned but not cited (2)

  1. An improved protein structure evaluation using a semi-empirically derived structure property. Pal MK, Lahiri T, Tanwar G, Kumar R. BMC Struct Biol 18 16 (2018)
  2. Hypothesis-free phenotype prediction within a genetics-first framework. Lu C, Zaucha J, Gam R, Fang H, Ben Smithers, Oates ME, Bernabe-Rubio M, Williams J, Zelenka N, Pandurangan AP, Tandon H, Shihab H, Kalaivani R, Sung M, Sardar AJ, Tzovoras BG, Danovi D, Gough J. Nat Commun 14 919 (2023)


Reviews citing this publication (6)

  1. Relaxin family peptides and their receptors. Bathgate RA, Halls ML, van der Westhuizen ET, Callander GE, Kocan M, Summers RJ. Physiol Rev 93 405-480 (2013)
  2. International Union of Basic and Clinical Pharmacology. XCV. Recent advances in the understanding of the pharmacology and biological roles of relaxin family peptide receptors 1-4, the receptors for relaxin family peptides. Halls ML, Bathgate RA, Sutton SW, Dschietzig TB, Summers RJ. Pharmacol Rev 67 389-440 (2015)
  3. Biological role and clinical significance of insulin-like peptide 3. Ivell R, Anand-Ivell R. Curr Opin Endocrinol Diabetes Obes 18 210-216 (2011)
  4. Synthetic relaxins. Hossain MA, Wade JD. Curr Opin Chem Biol 22 47-55 (2014)
  5. Genetic analysis of the human Insulin-like 3 gene: absence of mutations in a Greek paediatric cohort with testicular maldescent. Mamoulakis C, Georgiou I, Dimitriadis F, Tsounapi P, Giannakis I, Chatzikyriakidou A, Antypas S, Sofras F, Takenaka A, Sofikitis N. Andrologia 46 986-996 (2014)
  6. In a Class of Their Own - RXFP1 and RXFP2 are Unique Members of the LGR Family. Petrie EJ, Lagaida S, Sethi A, Bathgate RA, Gooley PR. Front Endocrinol (Lausanne) 6 137 (2015)

Articles citing this publication (27)

  1. Synthesis, conformation, and activity of human insulin-like peptide 5 (INSL5). Akhter Hossain M, Bathgate RA, Kong CK, Shabanpoor F, Zhang S, Haugaard-Jönsson LM, Rosengren KJ, Tregear GW, Wade JD. Chembiochem 9 1816-1822 (2008)
  2. Origin of INSL3-mediated testicular descent in therian mammals. Park JI, Semyonov J, Chang CL, Yi W, Warren W, Hsu SY. Genome Res 18 974-985 (2008)
  3. Structure of the R3/I5 chimeric relaxin peptide, a selective GPCR135 and GPCR142 agonist. Haugaard-Jönsson LM, Hossain MA, Daly NL, Bathgate RA, Wade JD, Craik DJ, Rosengren KJ. J Biol Chem 283 23811-23818 (2008)
  4. Solid phase synthesis and structural analysis of novel A-chain dicarba analogs of human relaxin-3 (INSL7) that exhibit full biological activity. Hossain MA, Rosengren KJ, Zhang S, Bathgate RA, Tregear GW, van Lierop BJ, Robinson AJ, Wade JD. Org Biomol Chem 7 1547-1553 (2009)
  5. The different ligand-binding modes of relaxin family peptide receptors RXFP1 and RXFP2. Scott DJ, Rosengren KJ, Bathgate RA. Mol Endocrinol 26 1896-1906 (2012)
  6. The minimal active structure of human relaxin-2. Hossain MA, Rosengren KJ, Samuel CS, Shabanpoor F, Chan LJ, Bathgate RA, Wade JD. J Biol Chem 286 37555-37565 (2011)
  7. INSL3 stimulates spermatogonial differentiation in testis of adult zebrafish (Danio rerio). Assis LH, Crespo D, Morais RD, França LR, Bogerd J, Schulz RW. Cell Tissue Res 363 579-588 (2016)
  8. Regulation of receptor signaling by relaxin A chain motifs: derivation of pan-specific and LGR7-specific human relaxin analogs. Park JI, Semyonov J, Yi W, Chang CL, Hsu SY. J Biol Chem 283 32099-32109 (2008)
  9. Loss of RXFP2 and INSL3 genes in Afrotheria shows that testicular descent is the ancestral condition in placental mammals. Sharma V, Lehmann T, Stuckas H, Funke L, Hiller M. PLoS Biol 16 e2005293 (2018)
  10. Identification of key residues essential for the structural fold and receptor selectivity within the A-chain of human gene-2 (H2) relaxin. Chan LJ, Rosengren KJ, Layfield SL, Bathgate RA, Separovic F, Samuel CS, Hossain MA, Wade JD. J Biol Chem 287 41152-41164 (2012)
  11. Identification of hydrophobic interactions between relaxin-3 and its receptor RXFP3: implication for a conformational change in the B-chain C-terminus during receptor binding. Hu MJ, Shao XX, Wang JH, Wei D, Liu YL, Xu ZG, Guo ZY. Amino Acids 48 2227-2236 (2016)
  12. Design, synthesis and pharmacological evaluation of cyclic mimetics of the insulin-like peptide 3 (INSL3) B-chain. Shabanpoor F, Bathgate RA, Hossain MA, Giannakis E, Wade JD, Hughes RA. J Pept Sci 13 113-120 (2007)
  13. Recombinant expression of an insulin-like peptide 3 (INSL3) precursor and its enzymatic conversion to mature human INSL3. Luo X, Bathgate RA, Liu YL, Shao XX, Wade JD, Guo ZY. FEBS J 276 5203-5211 (2009)
  14. Dimerization and negative cooperativity in the relaxin family peptide receptors. Svendsen AM, Vrecl M, Knudsen L, Heding A, Wade JD, Bathgate RA, De Meyts P, Nøhr J. Ann N Y Acad Sci 1160 54-59 (2009)
  15. Design and development of analogues of dimers of insulin-like peptide 3 B-chain as high-affinity antagonists of the RXFP2 receptor. Shabanpoor F, Zhang S, Hughes RA, Hossain MA, Layfield S, Ferraro T, Bathgate RA, Separovic F, Wade JD. Biopolymers 96 81-87 (2011)
  16. The structural determinants of insulin-like Peptide 3 activity. Bathgate RA, Zhang S, Hughes RA, Rosengren KJ, Wade JD. Front Endocrinol (Lausanne) 3 11 (2012)
  17. Effect of helix-promoting strategies on the biological activity of novel analogues of the B-chain of INSL3. Shabanpoor F, Hughes RA, Zhang S, Bathgate RA, Layfield S, Hossain MA, Tregear GW, Separovic F, Wade JD. Amino Acids 38 121-131 (2010)
  18. Total Solid-Phase Synthesis of Biologically Active Drosophila Insulin-Like Peptide 2 (DILP2). Lin F, Hossain MA, Post S, Karashchuk G, Tatar M, De Meyts P, Wade JD. Aust J Chem 70 208-212 (2017)
  19. Structural insights into the function of relaxins. Rosengren KJ, Bathgate RA, Craik DJ, Daly NL, Haugaard-Jönsson LM, Hossain MA, Wade JD. Ann N Y Acad Sci 1160 20-26 (2009)
  20. The chemical synthesis of relaxin and related peptides. Wade JD, Lin F, Hossain MA, Shabanpoor F, Zhang S, Tregear GW. Ann N Y Acad Sci 1160 11-15 (2009)
  21. Distinct activation modes of the Relaxin Family Peptide Receptor 2 in response to insulin-like peptide 3 and relaxin. Bruell S, Sethi A, Smith N, Scott DJ, Hossain MA, Wu QP, Guo ZY, Petrie EJ, Gooley PR, Bathgate RAD. Sci Rep 7 3294 (2017)
  22. Structure and activity in the relaxin family of peptides. Tregear GW, Bathgate RA, Hossain MA, Lin F, Zhang S, Shabanpoor F, Scott DJ, Ma S, Gundlach AL, Samuel CS, Wade JD. Ann N Y Acad Sci 1160 5-10 (2009)
  23. In vitro degradation of insulin-like peptide 3 by insulin-degrading enzyme. Zhang WJ, Luo X, Guo ZY. Protein J 29 93-98 (2010)
  24. Solution structure of a conformationally restricted fully active derivative of the human relaxin-like factor. Büllesbach EE, Hass MA, Jensen MR, Hansen DF, Kristensen SM, Schwabe C, Led JJ. Biochemistry 47 13308-13317 (2008)
  25. De novo design and synthesis of cyclic and linear peptides to mimic the binding cassette of human relaxin. Hossain MA, Bathgate RA, Tregear G, Wade JD. Ann N Y Acad Sci 1160 16-19 (2009)
  26. Orthosteric, Allosteric and Biased Signalling at the Relaxin-3 Receptor RXFP3. Kocan M, Ang SY, Summers RJ. Neurochem Res 41 610-619 (2016)
  27. The "hot wires" of the relaxin-like factor (Insl3). Schwabe C, Büllesbach EE. Ann N Y Acad Sci 1160 93-98 (2009)


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