title: Platelet factor 4 and interleukin-8 CXC chemokine heterodimer formation modulates function at the quaternary structural level.
abstract: The apparent complexity of biology increases as more biomolecular interactions that mediate function become known. We have used NMR spectroscopy and molecular modeling to provide direct evidence that tetrameric platelet factor-4 (PF4) and dimeric interleukin-8 (IL8), two members of the CXC chemokine family, readily interact by exchanging subunits and forming heterodimers via extension of their antiparallel beta-sheet domains. We further demonstrate using functional assays that PF4/IL8 heterodimerization has a direct and significant consequence on the biological activity of both chemokines. Formation of heterodimers enhances the anti-proliferative effect of PF4 on endothelial cells in culture, as well as the IL8-induced migration of CXCR2 vector-transfected Baf3 cells. These results suggest that CXC chemokine biology, and perhaps cytokine biology in general, may be functionally modulated at the molecular level by formation of heterodimers. This concept, in turn, has implications for designing chemokine/cytokine variants with modified biological properties.
authors.affiliation: Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, Minnesota 55455, USA.
authors.forename: Irina V
authors.initials: IV
authors.lastname: Nesmelova
authors.forename: Yuk
authors.initials: Y
authors.lastname: Sham
authors.forename: Arkadiusz Z
authors.initials: AZ
authors.lastname: Dudek
authors.forename: Loes I
authors.initials: LI
authors.lastname: van Eijk
authors.forename: Guoping
authors.initials: G
authors.lastname: Wu
authors.forename: Arne
authors.initials: A
authors.lastname: Slungaard
authors.forename: Frank
authors.initials: F
authors.lastname: Mortari
authors.forename: Arjan W
authors.initials: AW
authors.lastname: Griffioen
authors.forename: Kevin H
authors.initials: KH
authors.lastname: Mayo
mesh_terms: D000818:Animals; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D018925:Chemokines / Q000737:chemistry / Q000378:metabolism; D019743:Chemokines, CXC / Q000378:metabolism*; D002633:Chemotaxis; D016207:Cytokines / Q000737:chemistry / Q000378:metabolism; D004058:Diffusion; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D004727:Endothelium / Q000166:cytology; D005822:Genetic Vectors; D006801:Humans; D016209:Interleukin-8 / Q000737:chemistry / Q000378:metabolism*; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008956:Models, Chemical; D010978:Platelet Factor 4 / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D023062:Receptors, Interleukin-8A / Q000235:genetics; D023063:Receptors, Interleukin-8B / Q000737:chemistry; D014162:Transfection; D014471:Umbilical Veins / Q000166:cytology
chemical_list: D018925:Chemokines; D019743:Chemokines, CXC; D016207:Cytokines; D016209:Interleukin-8; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B; D010978:Platelet Factor 4