Chemokines

Structural features

Most chemokines are secreted proteins, although membrane-bound forms also exist that act as adhesion molecules (e.g., fractalkine). In biological fluids, they typically exist as homo- or heterodimers, and less commonly as tetramers.

The spatial organization of a chemokine includes an N-terminal region, an N-loop, a core domain (composed of β-sheets), and a C-terminal α-helix. Interestingly, the dimerization of $\alpha$-chemokines forms a broad surface that visually resembles the peptide-binding region in major histocompatibility complex (MHC) molecules.

To guide cells, chemokines must establish a concentration gradient. To achieve this, they bind to glycosaminoglycans (heparin, chondroitin sulfate) on the cell surface or in the extracellular matrix. If metalloproteinase enzymes cleave the individual N-terminal portion from the molecule, the chemokine is converted into an inhibitor.

Classification of chemokines

The structural classification is based on the relative position of cysteine (C) residues near the N-terminus of the molecule. Four groups are distinguished:

1. $\alpha$-chemokines (CXC chemokines): two cysteine residues are separated by any single amino acid. Genes for this group are localized on chromosome 4q. They predominantly recruit neutrophils (sometimes lymphocytes, but not monocytes). Within the group, a subgroup of ELR-positive chemokines is distinguished, which can stimulate angiogenesis.
2. $\beta$-chemokines (CC chemokines): cysteine residues are adjacent to each other. Genes are located mainly on chromosome 17q. Their target cells are monocytes and lymphocytes (but not neutrophils).
3. $\gamma$-chemokines (C chemokines): a minor group with only two cysteine residues in the molecule. Genes are on chromosome 1q.
4. $\delta$-chemokines (CX$_3$C chemokines): a minor group (the sole representative is fractalkine) where the cysteines are separated by three amino acids. Genes are on chromosome 16q.

Within the same group, the primary protein structure shares 70–90% identity, whereas homology between different groups does not exceed 40%.

Functional division

Based on synthesis and secretion conditions, chemokines are divided into two main categories:

• Homeostatic. Secreted continuously (mainly by stromal and endothelial cells). They are responsible for the baseline distribution of lymphocytes in healthy tissues. For example, they direct T-cell precursors to the thymus, ensure their movement during maturation, and strictly distribute B and T lymphocytes to their respective zones in lymph nodes.
• Proinflammatory. Produced in response to stimuli—direct action of pathogens or the influence of proinflammatory cytokines (IL-1, TNF$\alpha$). Their task is to activate leukocytes and recruit them to the site of inflammation. They can be synthesized in advance and stored in leukocyte granules, being released upon degranulation.

Chemokine receptors and signal transduction

Chemokine receptors belong to the GPCR (G protein-coupled receptors) family. These are 7-transmembrane proteins whose extracellular portion recognizes the ligand, while the intracellular portion is coupled to intracellular G proteins. The receptor system is redundant: a single receptor can bind multiple different chemokines, and vice versa.

When a chemokine binds to its receptor, receptor dimerization and G protein activation occur (GDP is exchanged for GTP). The heterotrimeric G protein dissociates into two active parts:

• The $\beta\gamma$ dimer activates enzymes (phospholipase C and PI-3K), leading to calcium release and the activation of guanine nucleotide exchange factors (GEFs). Ultimately, the small GTPase Rac is activated, which is essential for cytoskeletal remodeling and migration.
• The GTP-bound $\alpha$ chain prepares the cell for movement by activating myosin II and integrins to enhance adhesion.

The protein Cdc42 is responsible for the direction of cell movement, initiating the assembly of F-actin at the leading edge of the cell (lamellipodia formation).

Briefly: answers to topical questions

Class and exam questions

What else to study on this topic

• Detailed mechanism of G protein function and the GTP ↔ GDP cycle
• The role of Cdc42, Rac, and Rap1 proteins in actin cytoskeleton remodeling
• Features of receptor expression in different types of inflammation (allergic, acute, macrophage-mediated)
• The effect of tetanus toxin on intracellular signal transduction from receptors
• The diverse effects of interleukin-8 (CXCL8) in acute inflammation

Other topics in the "Innate Immunity" section

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