title: The CXCL12gamma chemokine displays unprecedented structural and functional properties that make it a paradigm of chemoattractant proteins.
abstract: 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.
authors.affiliation: Departamento de Biología Experimental, Universidad de Jaén, Jaén, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Rueda
authors.forename: Karl
authors.initials: K
authors.lastname: Balabanian
authors.forename: Bernard
authors.initials: B
authors.lastname: Lagane
authors.forename: Isabelle
authors.initials: I
authors.lastname: Staropoli
authors.forename: Ken
authors.initials: K
authors.lastname: Chow
authors.forename: Angelique
authors.initials: A
authors.lastname: Levoye
authors.forename: Cedric
authors.initials: C
authors.lastname: Laguri
authors.forename: Rabia
authors.initials: R
authors.lastname: Sadir
authors.forename: Thierry
authors.initials: T
authors.lastname: Delaunay
authors.forename: Elena
authors.initials: E
authors.lastname: Izquierdo
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: Pablos
authors.forename: Elena
authors.initials: E
authors.lastname: Lendinez
authors.forename: Antonio
authors.initials: A
authors.lastname: Caruz
authors.forename: Diego
authors.initials: D
authors.lastname: Franco
authors.forename: Françoise
authors.initials: F
authors.lastname: Baleux
authors.forename: Hugues
authors.initials: H
authors.lastname: Lortat-Jacob
authors.forename: Fernando
authors.initials: F
authors.lastname: Arenzana-Seisdedos
mesh_terms: D000818:Animals; D016466:CHO Cells; D002465:Cell Movement; D054377:Chemokine CXCL12 / Q000737:chemistry / Q000502:physiology*; D002630:Chemotactic Factors / Q000737:chemistry*; D003094:Collagen / Q000737:chemistry; D006224:Cricetinae; D003412:Cricetulus; D004338:Drug Combinations; D006025:Glycosaminoglycans / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D007797:Laminin / Q000737:chemistry; D051379:Mice; D011485:Protein Binding; D011509:Proteoglycans / Q000737:chemistry; D019718:Receptors, CXCR4 / Q000737:chemistry; D020349:Surface Plasmon Resonance
chemical_list: D054377:Chemokine CXCL12; D002630:Chemotactic Factors; D004338:Drug Combinations; D006025:Glycosaminoglycans; D007797:Laminin; D011509:Proteoglycans; D019718:Receptors, CXCR4; C059485:matrigel; D003094:Collagen