Chemokine CXCL1 dimer is a potent agonist for the CXCR2 receptor

Aishwarya Ravindran, Kirti V. Sawant, Jose Sarmiento, Javier Navarro, Krishna Rajarathnam

    Research output: Contribution to journalArticlepeer-review

    56 Scopus citations

    Abstract

    The CXCL1/CXCR2 axis plays a crucial role in recruiting neutrophils in response to microbial infection and tissue injury, and dysfunction in this process has been implicated in various inflammatory diseases. Chemokines exist as monomers and dimers, and compelling evidence now exists that both forms regulate in vivo function. Therefore, knowledge of the receptor activities of both CXCL1 monomer and dimer is essential to describe the molecular mechanisms by which they orchestrate neutrophil function. The monomer-dimer equilibrium constant (∼20 μm) and the CXCR2 binding constant (1 nM) indicate that WT CXCL1 is active as a monomer. To characterize dimer activity, we generated a trapped dimer by introducing a disulfide across the dimer interface. This disulfide-linked CXCL1 dimer binds CXCR2 with nanomolar affinity and shows potent agonist activity in various cellular assays. We also compared the receptor binding mechanism of this dimer with that of a CXCL1 monomer, generated by deleting the C-terminal residues that stabilize the dimer interface. We observe that the binding interactions of the dimer and monomer to the CXCR2 N-termi-nal domain, which plays an important role in determining affinity and activity, are essentially conserved. The potent activity of the CXCL1 dimer is novel: dimers of the CC chemokines CCL2 and CCL4 are inactive, and the dimer of the CXC chemokine CXCL8 (which is closely related to CXCL1) is marginally active for CXCR1 but shows variable activity for CXCR2. We conclude that large differences in dimer activity among different chemo-kine-receptor pairs have evolved for fine-tuned leukocyte function.

    Original languageEnglish (US)
    Pages (from-to)12244-12252
    Number of pages9
    JournalJournal of Biological Chemistry
    Volume288
    Issue number17
    DOIs
    StatePublished - Apr 26 2013

    ASJC Scopus subject areas

    • Biochemistry
    • Molecular Biology
    • Cell Biology

    Fingerprint

    Dive into the research topics of 'Chemokine CXCL1 dimer is a potent agonist for the CXCR2 receptor'. Together they form a unique fingerprint.

    Cite this