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Review
. 2023 Jul 19;24(14):11639.
doi: 10.3390/ijms241411639.

Heterodimers Are an Integral Component of Chemokine Signaling Repertoire

Kimia Kaffashi  1   2 , Didier Dréau  1 , Irina V Nesmelova  2   3
Affiliations
Review

Heterodimers Are an Integral Component of Chemokine Signaling Repertoire

Kimia Kaffashi et al. Int J Mol Sci. .

Abstract

Chemokines are a family of signaling proteins that play a crucial role in cell-cell communication, cell migration, and cell trafficking, particularly leukocytes, under both normal and pathological conditions. The oligomerization state of chemokines influences their biological activity. The heterooligomerization occurs when multiple chemokines spatially and temporally co-localize, and it can significantly affect cellular responses. Recently, obligate heterodimers have emerged as tools to investigate the activities and molecular mechanisms of chemokine heterodimers, providing valuable insights into their functional roles. This review focuses on the latest progress in understanding the roles of chemokine heterodimers and their contribution to the functioning of the chemokine network.

Keywords: binding; chemokine; chemokine receptor; glycosaminoglycan; heterodimer; heteromer; oligomerization; signaling; structure; synergy.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
(A) Schematic representation of chemokine monomer. Key features are labeled, including N-terminus; N-loop; beta strands β1–β3; alpha-helix H1; 30s, 40s, and 50s loops. Conserved cysteines are shown, and disulfide bonds between them are indicated by dashed lines. (B) Structures of CXC (CXCL12, pdb code 2NWG) and CC (CCL5, pdb code 5COY) chemokine homodimers. The monomers are shown in different shades. (C) Structural models of CXC (CXCL4-CXCL12) and CC (CXCL4-CCL5) heterodimers. The CXCL4 monomer is shown in green, while the CXCL12 and CCL5 monomers are shown in the same color as in panel B. In CXCL4-CCL5 heterodimer, interface residues are highlighted in red. These residues were determined as those that are located within 4 Å of the opposite monomer.
Figure 2
Figure 2
(Left) Structural model of the CXCL4–CXCL12 heterodimer. The CXCL4 monomer is shown in green and the CXCL12 monomer is shown in purple. The intermonomer interface formed by the two β1 strands is highlighted, and residues selected for cysteine substitution are labeled and shown in orange with side chains. (Right) The amino acid sequence and the direction of the first β1 strand are shown with the axis of symmetry indicated by dashed line. Residues S26 and L29, selected for cysteine substitution, are away from the symmetry axis, preventing the formation of disulfide-linked homodimers.
Figure 3
Figure 3
(A) Structural model of the CXCL12 chemokine bound to the CXCR4 receptor generated using structures of CXCR4 in complex with a viral chemokine vMIP-II (pdb code 4RWS) and CXCR4 N-terminus in complex with CXCL12 (pdb code 2N55). (B) Structure of CXCL12 homodimer in complex with the N-terminus of CXCR4 (pdb code 2K04). (C) Structural model of CXCL12-CXCL4 heterodimer. The β1 strands are labeled.
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