title: Functional divergence between 2 chemokines is conferred by single amino acid change.
abstract: CXCL4 and CXCL4L1 are 2 closely related CXC chemokines that exhibit potent antiangiogenic activity. Because interactions with glycosaminoglycans play a crucial role in chemokines activity, we determined the binding parameters of CXCL4 and CXCL4L1 for heparin, heparan sulfate, and chondroitin sulfate B. We further demonstrated that the Leu67/His67 substitution is critical for the decrease in glycan binding of CXCL4L1 but also for the increase of its angiostatic activities. Using a set of mutants, we show that glycan affinity and angiostatic properties are not completely related. These data are reinforced using a monoclonal antibody that specifically recognizes structural modifications in CXCL4L1 due to the presence of His67 and that blocks its biologic activity. In vivo, half-life and diffusibility of CXCL4L1 compared with CXCL4 is strongly increased. As opposed to CXCL4L1, CXCL4 is preferentially retained at its site of expression. These findings establish that, despite small differences in the primary structure, CXCL4L1 is highly distinct from CXCL4. These observations are not only of great significance for the antiangiogenic activity of CXCL4L1 and for its potential use in clinical development but also for other biologic processes such as inflammation, thrombosis or tissue repair.
authors.affiliation: Insem, U920, Talence, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Dubrac
authors.forename: Cathy
authors.initials: C
authors.lastname: Quemener
authors.forename: Eric
authors.initials: E
authors.lastname: Lacazette
authors.forename: Fréderic
authors.initials: F
authors.lastname: Lopez
authors.forename: Catherine
authors.initials: C
authors.lastname: Zanibellato
authors.forename: Wen-Guey
authors.initials: WG
authors.lastname: Wu
authors.forename: Andréas
authors.initials: A
authors.lastname: Bikfalvi
authors.forename: Hervé
authors.initials: H
authors.lastname: Prats
mesh_terms: D000595:Amino Acid Sequence; D000596:Amino Acids / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002417:Cattle; D002460:Cell Line; D049109:Cell Proliferation; D003871:Dermatan Sulfate / Q000378:metabolism*; D006493:Heparin / Q000378:metabolism*; D006497:Heparan Sulfate / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D009154:Mutation; D018919:Neovascularization, Physiologic; D010978:Platelet Factor 4 / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D011994:Recombinant Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism
chemical_list: D000596:Amino Acids; D003871:Dermatan Sulfate; D006493:Heparin; D006497:Heparan Sulfate; D010978:Platelet Factor 4; D011994:Recombinant Proteins; C064936:PF4V1 protein, human