Structure-function relationship of an Urokinase Receptor-derived peptide which inhibits the Formyl Peptide Receptor type 1 activity

The interaction between the short 88Ser-Arg-Ser-Arg-Tyr92 sequence of the urokinase receptor (uPAR) and the formyl peptide receptor type 1 (FPR1) elicits cell migration. We generated the Ac-(D)-Tyr-(D)-Arg-Aib-(D)-Arg-NH2 (RI-3) peptide which inhibits the uPAR/FPR1 interaction, reducing migration of...

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Autores principales: Minopoli, Michele, Polo, Andrea, Ragone, Concetta, Ingangi, Vincenzo, Ciliberto, Gennaro, Pessi, Antonello, Sarno, Sabrina, Budillon, Alfredo, Costantini, Susan, Carriero, Maria Vincenza
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6704176/
https://www.ncbi.nlm.nih.gov/pubmed/31434916
http://dx.doi.org/10.1038/s41598-019-47900-3
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author Minopoli, Michele
Polo, Andrea
Ragone, Concetta
Ingangi, Vincenzo
Ciliberto, Gennaro
Pessi, Antonello
Sarno, Sabrina
Budillon, Alfredo
Costantini, Susan
Carriero, Maria Vincenza
author_facet Minopoli, Michele
Polo, Andrea
Ragone, Concetta
Ingangi, Vincenzo
Ciliberto, Gennaro
Pessi, Antonello
Sarno, Sabrina
Budillon, Alfredo
Costantini, Susan
Carriero, Maria Vincenza
author_sort Minopoli, Michele
collection PubMed
description The interaction between the short 88Ser-Arg-Ser-Arg-Tyr92 sequence of the urokinase receptor (uPAR) and the formyl peptide receptor type 1 (FPR1) elicits cell migration. We generated the Ac-(D)-Tyr-(D)-Arg-Aib-(D)-Arg-NH2 (RI-3) peptide which inhibits the uPAR/FPR1 interaction, reducing migration of FPR1 expressing cells toward N-formyl-methionyl-leucyl-phenylalanine (fMLF) and Ser-Arg-Ser-Arg-Tyr (SRSRY) peptides. To understand the structural basis of the RI-3 inhibitory effects, the FPR1/fMLF, FPR1/SRSRY and FPR1/RI-3 complexes were modeled and analyzed, focusing on the binding pocket of FPR1 and the interaction between the amino acids that signal to the FPR1 C-terminal loop. We found that RI-3 shares the same binding site of fMLF and SRSRY on FPR1. However, while fMLF and SRSRY display the same agonist activation signature (i.e. the series of contacts that transmit the conformational transition throughout the complex), translating binding into signaling, RI-3 does not interact with the activation region of FPR1 and hence does not activate signaling. Indeed, fluorescein-conjugated RI-3 prevents either fMLF and SRSRY uptake on FPR1 without triggering FPR1 internalization and cell motility in the absence of any stimulus. Collectively, our data show that RI-3 is a true FPR1 antagonist and suggest a pharmacophore model useful for development of compounds that selectively inhibit the uPAR-triggered, FPR1-mediated cell migration.
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spelling pubmed-67041762019-08-23 Structure-function relationship of an Urokinase Receptor-derived peptide which inhibits the Formyl Peptide Receptor type 1 activity Minopoli, Michele Polo, Andrea Ragone, Concetta Ingangi, Vincenzo Ciliberto, Gennaro Pessi, Antonello Sarno, Sabrina Budillon, Alfredo Costantini, Susan Carriero, Maria Vincenza Sci Rep Article The interaction between the short 88Ser-Arg-Ser-Arg-Tyr92 sequence of the urokinase receptor (uPAR) and the formyl peptide receptor type 1 (FPR1) elicits cell migration. We generated the Ac-(D)-Tyr-(D)-Arg-Aib-(D)-Arg-NH2 (RI-3) peptide which inhibits the uPAR/FPR1 interaction, reducing migration of FPR1 expressing cells toward N-formyl-methionyl-leucyl-phenylalanine (fMLF) and Ser-Arg-Ser-Arg-Tyr (SRSRY) peptides. To understand the structural basis of the RI-3 inhibitory effects, the FPR1/fMLF, FPR1/SRSRY and FPR1/RI-3 complexes were modeled and analyzed, focusing on the binding pocket of FPR1 and the interaction between the amino acids that signal to the FPR1 C-terminal loop. We found that RI-3 shares the same binding site of fMLF and SRSRY on FPR1. However, while fMLF and SRSRY display the same agonist activation signature (i.e. the series of contacts that transmit the conformational transition throughout the complex), translating binding into signaling, RI-3 does not interact with the activation region of FPR1 and hence does not activate signaling. Indeed, fluorescein-conjugated RI-3 prevents either fMLF and SRSRY uptake on FPR1 without triggering FPR1 internalization and cell motility in the absence of any stimulus. Collectively, our data show that RI-3 is a true FPR1 antagonist and suggest a pharmacophore model useful for development of compounds that selectively inhibit the uPAR-triggered, FPR1-mediated cell migration. Nature Publishing Group UK 2019-08-21 /pmc/articles/PMC6704176/ /pubmed/31434916 http://dx.doi.org/10.1038/s41598-019-47900-3 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Minopoli, Michele
Polo, Andrea
Ragone, Concetta
Ingangi, Vincenzo
Ciliberto, Gennaro
Pessi, Antonello
Sarno, Sabrina
Budillon, Alfredo
Costantini, Susan
Carriero, Maria Vincenza
Structure-function relationship of an Urokinase Receptor-derived peptide which inhibits the Formyl Peptide Receptor type 1 activity
title Structure-function relationship of an Urokinase Receptor-derived peptide which inhibits the Formyl Peptide Receptor type 1 activity
title_full Structure-function relationship of an Urokinase Receptor-derived peptide which inhibits the Formyl Peptide Receptor type 1 activity
title_fullStr Structure-function relationship of an Urokinase Receptor-derived peptide which inhibits the Formyl Peptide Receptor type 1 activity
title_full_unstemmed Structure-function relationship of an Urokinase Receptor-derived peptide which inhibits the Formyl Peptide Receptor type 1 activity
title_short Structure-function relationship of an Urokinase Receptor-derived peptide which inhibits the Formyl Peptide Receptor type 1 activity
title_sort structure-function relationship of an urokinase receptor-derived peptide which inhibits the formyl peptide receptor type 1 activity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6704176/
https://www.ncbi.nlm.nih.gov/pubmed/31434916
http://dx.doi.org/10.1038/s41598-019-47900-3
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