Chemokine Heteromers and Their Impact on Cellular Function-A Conceptual Framework

Abstract

Chemoattractant cytokines or chemokines are proteins involved in numerous biological activities. Their essential role consists of the formation of gradient and (immune) cell recruitment. Chemokine biology and its related signaling system is more complex than simple ligand-receptor interactions. Beside interactions with their cognate and/or atypical chemokine receptors, and glycosaminoglycans (GAGs), chemokines form complexes with themselves as homo-oligomers, heteromers and also with other soluble effector proteins, including the atypical chemokine MIF, carbohydrate-binding proteins (galectins), damage-associated molecular patterns (DAMPs) or with chemokine-binding proteins such as evasins. Likewise, nucleic acids have been described as binding targets for the tetrameric form of CXCL4. The dynamic balance between monomeric and dimeric structures, as well as interactions with GAGs, modulate the concentrations of free chemokines available along with the nature of the gradient. Dimerization of chemokines changes the canonical monomeric fold into two main dimeric structures, namely CC- and CXC-type dimers. Recent studies highlighted that chemokine dimer formation is a frequent event that could occur under pathophysiological conditions. The structural changes dictated by chemokine dimerization confer additional biological activities, e.g., biased signaling. The present review will provide a short overview of the known functionality of chemokines together with the consequences of the interactions engaged by the chemokines with other proteins. Finally, we will present potential therapeutic tools targeting the chemokine multimeric structures that could modulate their biological functions.

Keywords: chemokine; galectin; heterodimer; homodimer; protein–protein interactions; therapeutics.

Figure 1

Monomeric and dimeric structures of chemokines. (A) monomeric chemokines share a canonical conformation comprising an N-terminal 310-helix, three β-strands and a C-terminal α-helix. (B–D) CC-type dimers share an elongated feature ((B), PDB 2L9H), whereas CXC-type dimers shape into a globular structure with a six-strand-based β-sheet ((C), PDB 1RHP). The metamorphic protein XCL1 presents a unique dimeric folding with a four-strand β-sheet ((D), PDB 2N54).

Figure 2

Model of a synergistic switch from a CC-type to a CXC-type dimer. (Left): CC-type CCL2 homodimer (blue and yellow, PDB 1DOL) is unable to bind CCR2 (purple, PDB 7XA3) due to the overlapping chemokine regions involved in both homodimeric formation and receptor binding. (Right): a chemokine (e.g., CXCL4 in green, PDB 1RHP) competes and displaces the dimer leading to the generation of a new homodimer (CXC-type in blue and green) with the release of free monomeric CCL2 (yellow). In this case, both monomeric CCL2 and the CXC-type homodimer are potentially able to bind to CCR2.