%0 Journal Article
%T The CXCL12¦Ã Chemokine Displays Unprecedented Structural and Functional Properties that Make It a Paradigm of Chemoattractant Proteins
%A Patricia Rueda
%A Karl Balabanian
%A Bernard Lagane
%A Isabelle Staropoli
%A Ken Chow
%A Angelique Levoye
%A Cedric Laguri
%A Rabia Sadir
%A Thierry Delaunay
%A Elena Izquierdo
%A Jose Luis Pablos
%A Elena Lendinez
%A Antonio Caruz
%A Diego Franco
%A Fran£¿oise Baleux
%A Hugues Lortat-Jacob
%A Fernando Arenzana-Seisdedos
%J PLOS ONE
%D 2008
%I Public Library of Science (PLoS)
%R 10.1371/journal.pone.0002543
%X The CXCL12¦Ã 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. CXCL12¦Ã 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 CXCL12¦Ã 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 CXCL12¦Ã both in mouse and human tissues, where it showed discrete differential expression. As an unprecedented feature among chemokines, the secreted CXCL12¦Ã 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 CXCL12¦Ã one of the higher affinity for HS (Kd = 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 CXCL12¦Ã to HS enabled it to promote in vivo intraperitoneal leukocyte accumulation and angiogenesis in matrigel plugs with much higher efficiency than CXCL12¦Á. In good agreement, mutant CXCL12¦Ã chemokines selectively devoid of HS-binding capacity failed to promote in vivo significant cell recruitment. We conclude that CXCL12¦Ã 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 CXCL12¦Ã the paradigm of haptotactic proteins, which regulate essential homeostatic functions by promoting directional migration and selective tissue homing of cells.
%U http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0002543