Platelet factor 4 and interleukin-8 CXC chemokine heterodimer formation modulates function at the quaternary structural level

Irina V. Nesmelova, Yuk Sham, Arkadiusz Z. Dudek, Loes I. Van Eijk, Guoping Wu, Arne Slungaard, Frank Mortari, Arjan W. Griffioen, Kevin H. Mayo

Research output: Contribution to journalArticlepeer-review

73 Scopus citations

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 β-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.

Original languageEnglish (US)
Pages (from-to)4948-4958
Number of pages11
JournalJournal of Biological Chemistry
Volume280
Issue number6
DOIs
StatePublished - Feb 11 2005

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