Structural and agonist properties of XCL2, the other member of the C-chemokine subfamily

Cytokine. 2015 Feb;71(2):302-11. doi: 10.1016/j.cyto.2014.11.010. Epub 2014 Dec 11.


Known for its unusual metamorphic native state structure, XCL1 has been the focus of most efforts to elucidate the structural, functional, and physiological properties of chemokines in the C subfamily. By comparison, its closely related paralog XCL2 remains virtually uncharacterized. Based on the importance of the chemokine N-terminus in receptor activation, it was hypothesized that two amino acid differences in XCL2 would alter its agonist activity relative to XCL1 for their shared receptor XCR1. This present study reveals several properties of XCL2 that were unexamined until now. Structurally, XCL1 and XCL2 are very similar, exchanging between the monomeric chemokine fold and an unrelated dimeric state under physiological NaCl and temperature conditions. Ca(2+) flux, chemotaxis, and heparin binding assays showed that the monomer form of XCL2 is responsible for G protein-coupled receptor activation while the dimeric form is important for GAG binding. Despite their high structural similarity, XCL2 displays a slightly higher affinity for heparin than XCL1. Because their in vitro functional profiles are virtually identical, distinct physiological roles for XCL1 and XCL2 are probably encoded at the level of expression.

Keywords: Ca(2+) flux; Chemotaxis; Lymphotactin; XCL1; XCL2.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Calcium / metabolism
  • Chemokines, C / chemistry*
  • Chemotaxis
  • Computational Biology
  • Heparin / chemistry
  • Humans
  • Hydrogen-Ion Concentration
  • Kinetics
  • Lymphokines / metabolism
  • Magnetic Resonance Spectroscopy
  • Molecular Sequence Data
  • Protein Binding
  • Protein Denaturation
  • Protein Multimerization
  • Protein Structure, Tertiary
  • Sequence Homology, Amino Acid
  • Sialoglycoproteins / metabolism
  • Signal Transduction
  • Sodium Chloride / chemistry
  • Temperature
  • Thermodynamics
  • Urea / chemistry


  • Chemokines, C
  • Lymphokines
  • Sialoglycoproteins
  • XCL1 protein, human
  • XCL2 protein, human
  • lymphotactin
  • Sodium Chloride
  • Urea
  • Heparin
  • Calcium