Multiple Active States and Oligomerization of CCR5 Revealed by Functional Properties of Monoclonal Antibodies

CC-chemokine receptor 5 (CCR5) is the principal coreceptor for macrophage-tropic strains of human immunodeficiency virus type 1 (HIV-1). We have generated a set of anti-CCR5 monoclonal antibodies and characterized them in terms of epitope recognition, competition with chemokine binding, receptor act...

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Prif Awduron: Blanpain, Cédric, Vanderwinden, Jean-Marie, Cihak, Josef, Wittamer, Valérie, Le Poul, Emmanuel, Issafras, Hassan, Stangassinger, Manfred, Vassart, Gilbert, Marullo, Stefano, Schloō̈ndorff, Detlef, Parmentier, Marc, Mack, Matthias
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Cyhoeddwyd: The American Society for Cell Biology 2002
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Mynediad Ar-lein:https://ncbi.nlm.nih.gov/pmc/articles/PMC65662/
https://ncbi.nlm.nih.gov/pubmed/11854425
https://ncbi.nlm.nih.govhttp://dx.doi.org/10.1091/mbc.01-03-0129
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spelling pubmed-656622002-04-22 Multiple Active States and Oligomerization of CCR5 Revealed by Functional Properties of Monoclonal Antibodies Blanpain, Cédric Vanderwinden, Jean-Marie Cihak, Josef Wittamer, Valérie Le Poul, Emmanuel Issafras, Hassan Stangassinger, Manfred Vassart, Gilbert Marullo, Stefano Schloō̈ndorff, Detlef Parmentier, Marc Mack, Matthias Mol Biol Cell Article CC-chemokine receptor 5 (CCR5) is the principal coreceptor for macrophage-tropic strains of human immunodeficiency virus type 1 (HIV-1). We have generated a set of anti-CCR5 monoclonal antibodies and characterized them in terms of epitope recognition, competition with chemokine binding, receptor activation and trafficking, and coreceptor activity. MC-4, MC-5, and MC-7 mapped to the amino-terminal domain, MC-1 to the second extracellular loop, and MC-6 to a conformational epitope covering multiple extracellular domains. MC-1 and MC-6 inhibited regulated on activation normal T cell expressed and secreted (RANTES), macrophage inflammatory polypeptide-1β, and Env binding, whereas MC-5 inhibited macrophage inflammatory polypeptide-1β and Env but not RANTES binding. MC-6 induced signaling in different functional assays, suggesting that this monoclonal antibody stabilizes an active conformation of CCR5. Flow cytometry and real-time confocal microscopy showed that MC-1 promoted strong CCR5 endocytosis. MC-1 but not its monovalent isoforms induced an increase in the transfer of energy between CCR5 molecules. Also, its monovalent isoforms bound efficiently, but did not internalize the receptor. In contrast, MC-4 did not prevent RANTES binding or subsequent signaling, but inhibited its ability to promote CCR5 internalization. These results suggest the existence of multiple active conformations of CCR5 and indicate that CCR5 oligomers are involved in an internalization process that is distinct from that induced by the receptor's agonists. The American Society for Cell Biology 2002-02 /pmc/articles/PMC65662/ /pubmed/11854425 http://dx.doi.org/10.1091/mbc.01-03-0129 Text en Copyright © 2002, The American Society for Cell Biology
institution US National Library of Medicine
collection PubMed Central
language en
format Article
topic Article
spellingShingle Article
Blanpain, Cédric
Vanderwinden, Jean-Marie
Cihak, Josef
Wittamer, Valérie
Le Poul, Emmanuel
Issafras, Hassan
Stangassinger, Manfred
Vassart, Gilbert
Marullo, Stefano
Schloō̈ndorff, Detlef
Parmentier, Marc
Mack, Matthias
Multiple Active States and Oligomerization of CCR5 Revealed by Functional Properties of Monoclonal Antibodies
description CC-chemokine receptor 5 (CCR5) is the principal coreceptor for macrophage-tropic strains of human immunodeficiency virus type 1 (HIV-1). We have generated a set of anti-CCR5 monoclonal antibodies and characterized them in terms of epitope recognition, competition with chemokine binding, receptor activation and trafficking, and coreceptor activity. MC-4, MC-5, and MC-7 mapped to the amino-terminal domain, MC-1 to the second extracellular loop, and MC-6 to a conformational epitope covering multiple extracellular domains. MC-1 and MC-6 inhibited regulated on activation normal T cell expressed and secreted (RANTES), macrophage inflammatory polypeptide-1β, and Env binding, whereas MC-5 inhibited macrophage inflammatory polypeptide-1β and Env but not RANTES binding. MC-6 induced signaling in different functional assays, suggesting that this monoclonal antibody stabilizes an active conformation of CCR5. Flow cytometry and real-time confocal microscopy showed that MC-1 promoted strong CCR5 endocytosis. MC-1 but not its monovalent isoforms induced an increase in the transfer of energy between CCR5 molecules. Also, its monovalent isoforms bound efficiently, but did not internalize the receptor. In contrast, MC-4 did not prevent RANTES binding or subsequent signaling, but inhibited its ability to promote CCR5 internalization. These results suggest the existence of multiple active conformations of CCR5 and indicate that CCR5 oligomers are involved in an internalization process that is distinct from that induced by the receptor's agonists.
author Blanpain, Cédric
Vanderwinden, Jean-Marie
Cihak, Josef
Wittamer, Valérie
Le Poul, Emmanuel
Issafras, Hassan
Stangassinger, Manfred
Vassart, Gilbert
Marullo, Stefano
Schloō̈ndorff, Detlef
Parmentier, Marc
Mack, Matthias
author_facet Blanpain, Cédric
Vanderwinden, Jean-Marie
Cihak, Josef
Wittamer, Valérie
Le Poul, Emmanuel
Issafras, Hassan
Stangassinger, Manfred
Vassart, Gilbert
Marullo, Stefano
Schloō̈ndorff, Detlef
Parmentier, Marc
Mack, Matthias
author_sort Blanpain, Cédric
title Multiple Active States and Oligomerization of CCR5 Revealed by Functional Properties of Monoclonal Antibodies
title_short Multiple Active States and Oligomerization of CCR5 Revealed by Functional Properties of Monoclonal Antibodies
title_full Multiple Active States and Oligomerization of CCR5 Revealed by Functional Properties of Monoclonal Antibodies
title_fullStr Multiple Active States and Oligomerization of CCR5 Revealed by Functional Properties of Monoclonal Antibodies
title_full_unstemmed Multiple Active States and Oligomerization of CCR5 Revealed by Functional Properties of Monoclonal Antibodies
title_sort multiple active states and oligomerization of ccr5 revealed by functional properties of monoclonal antibodies
publisher The American Society for Cell Biology
publisher_facet The American Society for Cell Biology
publishDate 2002
url https://ncbi.nlm.nih.gov/pmc/articles/PMC65662/
https://ncbi.nlm.nih.gov/pubmed/11854425
https://ncbi.nlm.nih.govhttp://dx.doi.org/10.1091/mbc.01-03-0129
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