The CXCL12gamma chemokine displays unprecedented structural and functional properties that make it a paradigm of chemoattractant proteins.

The CXCL12gamma 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. CXCL12gamma is formed by a protein core shared by all CXCL12 isoforms, extended by a highly cation...

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Autores principales: Patricia Rueda, Karl Balabanian, Bernard Lagane, Isabelle Staropoli, Ken Chow, Angelique Levoye, Cedric Laguri, Rabia Sadir, Thierry Delaunay, Elena Izquierdo, Jose Luis Pablos, Elena Lendinez, Antonio Caruz, Diego Franco, Françoise Baleux, Hugues Lortat-Jacob, Fernando Arenzana-Seisdedos
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Publicado: Public Library of Science (PLoS) 2008
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spelling oai:doaj.org-article:575c6fb3e913424fa7902048a0b736fb2021-11-25T06:11:45ZThe CXCL12gamma chemokine displays unprecedented structural and functional properties that make it a paradigm of chemoattractant proteins.1932-620310.1371/journal.pone.0002543https://doaj.org/article/575c6fb3e913424fa7902048a0b736fb2008-07-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/18648536/?tool=EBIhttps://doaj.org/toc/1932-6203The CXCL12gamma 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. CXCL12gamma 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 CXCL12gamma 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 CXCL12gamma both in mouse and human tissues, where it showed discrete differential expression. As an unprecedented feature among chemokines, the secreted CXCL12gamma 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 CXCL12gamma 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 CXCL12gamma to HS enabled it to promote in vivo intraperitoneal leukocyte accumulation and angiogenesis in matrigel plugs with much higher efficiency than CXCL12alpha. In good agreement, mutant CXCL12gamma chemokines selectively devoid of HS-binding capacity failed to promote in vivo significant cell recruitment. We conclude that CXCL12gamma 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 CXCL12gamma the paradigm of haptotactic proteins, which regulate essential homeostatic functions by promoting directional migration and selective tissue homing of cells.Patricia RuedaKarl BalabanianBernard LaganeIsabelle StaropoliKen ChowAngelique LevoyeCedric LaguriRabia SadirThierry DelaunayElena IzquierdoJose Luis PablosElena LendinezAntonio CaruzDiego FrancoFrançoise BaleuxHugues Lortat-JacobFernando Arenzana-SeisdedosPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 3, Iss 7, p e2543 (2008)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
Patricia Rueda
Karl Balabanian
Bernard Lagane
Isabelle Staropoli
Ken Chow
Angelique Levoye
Cedric Laguri
Rabia Sadir
Thierry Delaunay
Elena Izquierdo
Jose Luis Pablos
Elena Lendinez
Antonio Caruz
Diego Franco
Françoise Baleux
Hugues Lortat-Jacob
Fernando Arenzana-Seisdedos
The CXCL12gamma chemokine displays unprecedented structural and functional properties that make it a paradigm of chemoattractant proteins.
description The CXCL12gamma 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. CXCL12gamma 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 CXCL12gamma 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 CXCL12gamma both in mouse and human tissues, where it showed discrete differential expression. As an unprecedented feature among chemokines, the secreted CXCL12gamma 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 CXCL12gamma 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 CXCL12gamma to HS enabled it to promote in vivo intraperitoneal leukocyte accumulation and angiogenesis in matrigel plugs with much higher efficiency than CXCL12alpha. In good agreement, mutant CXCL12gamma chemokines selectively devoid of HS-binding capacity failed to promote in vivo significant cell recruitment. We conclude that CXCL12gamma 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 CXCL12gamma the paradigm of haptotactic proteins, which regulate essential homeostatic functions by promoting directional migration and selective tissue homing of cells.
format article
author Patricia Rueda
Karl Balabanian
Bernard Lagane
Isabelle Staropoli
Ken Chow
Angelique Levoye
Cedric Laguri
Rabia Sadir
Thierry Delaunay
Elena Izquierdo
Jose Luis Pablos
Elena Lendinez
Antonio Caruz
Diego Franco
Françoise Baleux
Hugues Lortat-Jacob
Fernando Arenzana-Seisdedos
author_facet Patricia Rueda
Karl Balabanian
Bernard Lagane
Isabelle Staropoli
Ken Chow
Angelique Levoye
Cedric Laguri
Rabia Sadir
Thierry Delaunay
Elena Izquierdo
Jose Luis Pablos
Elena Lendinez
Antonio Caruz
Diego Franco
Françoise Baleux
Hugues Lortat-Jacob
Fernando Arenzana-Seisdedos
author_sort Patricia Rueda
title The CXCL12gamma chemokine displays unprecedented structural and functional properties that make it a paradigm of chemoattractant proteins.
title_short The CXCL12gamma chemokine displays unprecedented structural and functional properties that make it a paradigm of chemoattractant proteins.
title_full The CXCL12gamma chemokine displays unprecedented structural and functional properties that make it a paradigm of chemoattractant proteins.
title_fullStr The CXCL12gamma chemokine displays unprecedented structural and functional properties that make it a paradigm of chemoattractant proteins.
title_full_unstemmed The CXCL12gamma chemokine displays unprecedented structural and functional properties that make it a paradigm of chemoattractant proteins.
title_sort cxcl12gamma chemokine displays unprecedented structural and functional properties that make it a paradigm of chemoattractant proteins.
publisher Public Library of Science (PLoS)
publishDate 2008
url https://doaj.org/article/575c6fb3e913424fa7902048a0b736fb
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