Cargando…

Identification of Key Receptor Residues Discriminating Human Chorionic Gonadotropin (hCG)- and Luteinizing Hormone (LH)-Specific Signaling

(1) The human luteinizing hormone (LH)/chorionic gonadotropin (hCG) receptor (LHCGR) discriminates its two hormone ligands and differs from the murine receptor (Lhr) in amino acid residues potentially involved in qualitative discerning of LH and hCG. The latter gonadotropin is absent in rodents. The...

Descripción completa

Detalles Bibliográficos
Autores principales: Lazzaretti, Clara, Secco, Valentina, Paradiso, Elia, Sperduti, Samantha, Rutz, Claudia, Kreuchwig, Annika, Krause, Gerd, Simoni, Manuela, Casarini, Livio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794846/
https://www.ncbi.nlm.nih.gov/pubmed/33375708
http://dx.doi.org/10.3390/ijms22010151
_version_ 1783634304730923008
author Lazzaretti, Clara
Secco, Valentina
Paradiso, Elia
Sperduti, Samantha
Rutz, Claudia
Kreuchwig, Annika
Krause, Gerd
Simoni, Manuela
Casarini, Livio
author_facet Lazzaretti, Clara
Secco, Valentina
Paradiso, Elia
Sperduti, Samantha
Rutz, Claudia
Kreuchwig, Annika
Krause, Gerd
Simoni, Manuela
Casarini, Livio
author_sort Lazzaretti, Clara
collection PubMed
description (1) The human luteinizing hormone (LH)/chorionic gonadotropin (hCG) receptor (LHCGR) discriminates its two hormone ligands and differs from the murine receptor (Lhr) in amino acid residues potentially involved in qualitative discerning of LH and hCG. The latter gonadotropin is absent in rodents. The aim of the study is to identify LHCGR residues involved in hCG/LH discrimination. (2) Eight LHCGR cDNAs were developed, carrying “murinizing” mutations on aminoacidic residues assumed to interact specifically with LH, hCG, or both. HEK293 cells expressing a mutant or the wild type receptor were treated with LH or hCG and the kinetics of cyclic adenosine monophosphate (cAMP) and phosphorylated extracellular signal-regulated kinases 1/2 (pERK1/2) activation was analyzed by bioluminescence resonance energy transfer (BRET). (3) Mutations falling within the receptor leucine reach repeat 9 and 10 (LRR9 and LRR10; K225S +T226I and R247T), of the large extracellular binding domain, are linked to loss of hormone-specific induced cAMP increase, as well as hCG-specific pERK1/2 activation, leading to a Lhr-like modulation of the LHCGR-mediated intracellular signaling pattern. These results support the hypothesis that LHCGR LRR domain is the interaction site of the hormone β-L2 loop, which differs between LH and hCG, and might be fundamental for inducing gonadotropin-specific signals. (4) Taken together, these data identify LHCGR key residues likely evolved in the human to discriminate LH/hCG specific binding.
format Online
Article
Text
id pubmed-7794846
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-77948462021-01-10 Identification of Key Receptor Residues Discriminating Human Chorionic Gonadotropin (hCG)- and Luteinizing Hormone (LH)-Specific Signaling Lazzaretti, Clara Secco, Valentina Paradiso, Elia Sperduti, Samantha Rutz, Claudia Kreuchwig, Annika Krause, Gerd Simoni, Manuela Casarini, Livio Int J Mol Sci Article (1) The human luteinizing hormone (LH)/chorionic gonadotropin (hCG) receptor (LHCGR) discriminates its two hormone ligands and differs from the murine receptor (Lhr) in amino acid residues potentially involved in qualitative discerning of LH and hCG. The latter gonadotropin is absent in rodents. The aim of the study is to identify LHCGR residues involved in hCG/LH discrimination. (2) Eight LHCGR cDNAs were developed, carrying “murinizing” mutations on aminoacidic residues assumed to interact specifically with LH, hCG, or both. HEK293 cells expressing a mutant or the wild type receptor were treated with LH or hCG and the kinetics of cyclic adenosine monophosphate (cAMP) and phosphorylated extracellular signal-regulated kinases 1/2 (pERK1/2) activation was analyzed by bioluminescence resonance energy transfer (BRET). (3) Mutations falling within the receptor leucine reach repeat 9 and 10 (LRR9 and LRR10; K225S +T226I and R247T), of the large extracellular binding domain, are linked to loss of hormone-specific induced cAMP increase, as well as hCG-specific pERK1/2 activation, leading to a Lhr-like modulation of the LHCGR-mediated intracellular signaling pattern. These results support the hypothesis that LHCGR LRR domain is the interaction site of the hormone β-L2 loop, which differs between LH and hCG, and might be fundamental for inducing gonadotropin-specific signals. (4) Taken together, these data identify LHCGR key residues likely evolved in the human to discriminate LH/hCG specific binding. MDPI 2020-12-25 /pmc/articles/PMC7794846/ /pubmed/33375708 http://dx.doi.org/10.3390/ijms22010151 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Lazzaretti, Clara
Secco, Valentina
Paradiso, Elia
Sperduti, Samantha
Rutz, Claudia
Kreuchwig, Annika
Krause, Gerd
Simoni, Manuela
Casarini, Livio
Identification of Key Receptor Residues Discriminating Human Chorionic Gonadotropin (hCG)- and Luteinizing Hormone (LH)-Specific Signaling
title Identification of Key Receptor Residues Discriminating Human Chorionic Gonadotropin (hCG)- and Luteinizing Hormone (LH)-Specific Signaling
title_full Identification of Key Receptor Residues Discriminating Human Chorionic Gonadotropin (hCG)- and Luteinizing Hormone (LH)-Specific Signaling
title_fullStr Identification of Key Receptor Residues Discriminating Human Chorionic Gonadotropin (hCG)- and Luteinizing Hormone (LH)-Specific Signaling
title_full_unstemmed Identification of Key Receptor Residues Discriminating Human Chorionic Gonadotropin (hCG)- and Luteinizing Hormone (LH)-Specific Signaling
title_short Identification of Key Receptor Residues Discriminating Human Chorionic Gonadotropin (hCG)- and Luteinizing Hormone (LH)-Specific Signaling
title_sort identification of key receptor residues discriminating human chorionic gonadotropin (hcg)- and luteinizing hormone (lh)-specific signaling
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794846/
https://www.ncbi.nlm.nih.gov/pubmed/33375708
http://dx.doi.org/10.3390/ijms22010151
work_keys_str_mv AT lazzaretticlara identificationofkeyreceptorresiduesdiscriminatinghumanchorionicgonadotropinhcgandluteinizinghormonelhspecificsignaling
AT seccovalentina identificationofkeyreceptorresiduesdiscriminatinghumanchorionicgonadotropinhcgandluteinizinghormonelhspecificsignaling
AT paradisoelia identificationofkeyreceptorresiduesdiscriminatinghumanchorionicgonadotropinhcgandluteinizinghormonelhspecificsignaling
AT sperdutisamantha identificationofkeyreceptorresiduesdiscriminatinghumanchorionicgonadotropinhcgandluteinizinghormonelhspecificsignaling
AT rutzclaudia identificationofkeyreceptorresiduesdiscriminatinghumanchorionicgonadotropinhcgandluteinizinghormonelhspecificsignaling
AT kreuchwigannika identificationofkeyreceptorresiduesdiscriminatinghumanchorionicgonadotropinhcgandluteinizinghormonelhspecificsignaling
AT krausegerd identificationofkeyreceptorresiduesdiscriminatinghumanchorionicgonadotropinhcgandluteinizinghormonelhspecificsignaling
AT simonimanuela identificationofkeyreceptorresiduesdiscriminatinghumanchorionicgonadotropinhcgandluteinizinghormonelhspecificsignaling
AT casarinilivio identificationofkeyreceptorresiduesdiscriminatinghumanchorionicgonadotropinhcgandluteinizinghormonelhspecificsignaling