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The CXCL12γ Chemokine Displays Unprecedented Structural and Functional Properties that Make It a Paradigm of Chemoattractant Proteins

The CXCL12γ chemokine arises by alternative splicing from Cxcl12, an essential gene during development. This protein binds CXCR4 and displays an exceptional degree of conservation (99%) in mammals. CXCL12γ is formed by a protein core shared by all CXCL12 isoforms, extended by a highly cationic carbo...

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Autores principales: Rueda, Patricia, Balabanian, Karl, Lagane, Bernard, Staropoli, Isabelle, Chow, Ken, Levoye, Angelique, Laguri, Cedric, Sadir, Rabia, Delaunay, Thierry, Izquierdo, Elena, Pablos, Jose Luis, Lendinez, Elena, Caruz, Antonio, Franco, Diego, Baleux, Françoise, Lortat-Jacob, Hugues, Arenzana-Seisdedos, Fernando
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2008
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2481281/
https://www.ncbi.nlm.nih.gov/pubmed/18648536
http://dx.doi.org/10.1371/journal.pone.0002543
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author Rueda, Patricia
Balabanian, Karl
Lagane, Bernard
Staropoli, Isabelle
Chow, Ken
Levoye, Angelique
Laguri, Cedric
Sadir, Rabia
Delaunay, Thierry
Izquierdo, Elena
Pablos, Jose Luis
Lendinez, Elena
Caruz, Antonio
Franco, Diego
Baleux, Françoise
Lortat-Jacob, Hugues
Arenzana-Seisdedos, Fernando
author_facet Rueda, Patricia
Balabanian, Karl
Lagane, Bernard
Staropoli, Isabelle
Chow, Ken
Levoye, Angelique
Laguri, Cedric
Sadir, Rabia
Delaunay, Thierry
Izquierdo, Elena
Pablos, Jose Luis
Lendinez, Elena
Caruz, Antonio
Franco, Diego
Baleux, Françoise
Lortat-Jacob, Hugues
Arenzana-Seisdedos, Fernando
author_sort Rueda, Patricia
collection PubMed
description The CXCL12γ chemokine arises by alternative splicing from Cxcl12, an essential gene during development. This protein binds CXCR4 and displays an exceptional degree of conservation (99%) in mammals. CXCL12γ is formed by a protein core shared by all CXCL12 isoforms, extended by a highly cationic carboxy-terminal (C-ter) domain that encompass four overlapped BBXB heparan sulfate (HS)-binding motifs. We hypothesize that this unusual domain could critically determine the biological properties of CXCL12γ through its interaction to, and regulation by extracellular glycosaminoglycans (GAG) and HS in particular. By both RT-PCR and immunohistochemistry, we mapped the localization of CXCL12γ both in mouse and human tissues, where it showed discrete differential expression. As an unprecedented feature among chemokines, the secreted CXCL12γ strongly interacted with cell membrane GAG, thus remaining mostly adsorbed on the plasmatic membrane upon secretion. Affinity chromatography and surface plasmon resonance allowed us to determine for CXCL12γ one of the higher affinity for HS (K(d) = 0.9 nM) ever reported for a protein. This property relies in the presence of four canonical HS-binding sites located at the C-ter domain but requires the collaboration of a HS-binding site located in the core of the protein. Interestingly, and despite reduced agonist potency on CXCR4, the sustained binding of CXCL12γ to HS enabled it to promote in vivo intraperitoneal leukocyte accumulation and angiogenesis in matrigel plugs with much higher efficiency than CXCL12α. In good agreement, mutant CXCL12γ chemokines selectively devoid of HS-binding capacity failed to promote in vivo significant cell recruitment. We conclude that CXCL12γ features unique structural and functional properties among chemokines which rely on the presence of a distinctive C-ter domain. The unsurpassed capacity to bind to HS on the extracellular matrix would make CXCL12γ the paradigm of haptotactic proteins, which regulate essential homeostatic functions by promoting directional migration and selective tissue homing of cells.
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spelling pubmed-24812812008-07-23 The CXCL12γ Chemokine Displays Unprecedented Structural and Functional Properties that Make It a Paradigm of Chemoattractant Proteins Rueda, Patricia Balabanian, Karl Lagane, Bernard Staropoli, Isabelle Chow, Ken Levoye, Angelique Laguri, Cedric Sadir, Rabia Delaunay, Thierry Izquierdo, Elena Pablos, Jose Luis Lendinez, Elena Caruz, Antonio Franco, Diego Baleux, Françoise Lortat-Jacob, Hugues Arenzana-Seisdedos, Fernando PLoS One Research Article The CXCL12γ chemokine arises by alternative splicing from Cxcl12, an essential gene during development. This protein binds CXCR4 and displays an exceptional degree of conservation (99%) in mammals. CXCL12γ is formed by a protein core shared by all CXCL12 isoforms, extended by a highly cationic carboxy-terminal (C-ter) domain that encompass four overlapped BBXB heparan sulfate (HS)-binding motifs. We hypothesize that this unusual domain could critically determine the biological properties of CXCL12γ through its interaction to, and regulation by extracellular glycosaminoglycans (GAG) and HS in particular. By both RT-PCR and immunohistochemistry, we mapped the localization of CXCL12γ both in mouse and human tissues, where it showed discrete differential expression. As an unprecedented feature among chemokines, the secreted CXCL12γ strongly interacted with cell membrane GAG, thus remaining mostly adsorbed on the plasmatic membrane upon secretion. Affinity chromatography and surface plasmon resonance allowed us to determine for CXCL12γ one of the higher affinity for HS (K(d) = 0.9 nM) ever reported for a protein. This property relies in the presence of four canonical HS-binding sites located at the C-ter domain but requires the collaboration of a HS-binding site located in the core of the protein. Interestingly, and despite reduced agonist potency on CXCR4, the sustained binding of CXCL12γ to HS enabled it to promote in vivo intraperitoneal leukocyte accumulation and angiogenesis in matrigel plugs with much higher efficiency than CXCL12α. In good agreement, mutant CXCL12γ chemokines selectively devoid of HS-binding capacity failed to promote in vivo significant cell recruitment. We conclude that CXCL12γ features unique structural and functional properties among chemokines which rely on the presence of a distinctive C-ter domain. The unsurpassed capacity to bind to HS on the extracellular matrix would make CXCL12γ the paradigm of haptotactic proteins, which regulate essential homeostatic functions by promoting directional migration and selective tissue homing of cells. Public Library of Science 2008-07-02 /pmc/articles/PMC2481281/ /pubmed/18648536 http://dx.doi.org/10.1371/journal.pone.0002543 Text en Rueda et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Rueda, Patricia
Balabanian, Karl
Lagane, Bernard
Staropoli, Isabelle
Chow, Ken
Levoye, Angelique
Laguri, Cedric
Sadir, Rabia
Delaunay, Thierry
Izquierdo, Elena
Pablos, Jose Luis
Lendinez, Elena
Caruz, Antonio
Franco, Diego
Baleux, Françoise
Lortat-Jacob, Hugues
Arenzana-Seisdedos, Fernando
The CXCL12γ Chemokine Displays Unprecedented Structural and Functional Properties that Make It a Paradigm of Chemoattractant Proteins
title The CXCL12γ Chemokine Displays Unprecedented Structural and Functional Properties that Make It a Paradigm of Chemoattractant Proteins
title_full The CXCL12γ Chemokine Displays Unprecedented Structural and Functional Properties that Make It a Paradigm of Chemoattractant Proteins
title_fullStr The CXCL12γ Chemokine Displays Unprecedented Structural and Functional Properties that Make It a Paradigm of Chemoattractant Proteins
title_full_unstemmed The CXCL12γ Chemokine Displays Unprecedented Structural and Functional Properties that Make It a Paradigm of Chemoattractant Proteins
title_short The CXCL12γ Chemokine Displays Unprecedented Structural and Functional Properties that Make It a Paradigm of Chemoattractant Proteins
title_sort cxcl12γ chemokine displays unprecedented structural and functional properties that make it a paradigm of chemoattractant proteins
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2481281/
https://www.ncbi.nlm.nih.gov/pubmed/18648536
http://dx.doi.org/10.1371/journal.pone.0002543
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