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Oligomerization State of CXCL4 Chemokines Regulates G Protein-Coupled Receptor Activation

Ya-Ping Chen, Hsin-Li Wu, Kevin Boyé1,2

  • 1INSERM U1029 , 33615 Pessac, France.

ACS Chemical Biology
|September 26, 2017
PubMed

Insights

The CXCL4 tetramer

Area of Science:

  • Biochemistry
  • Immunology
  • Molecular Biology

Background:

  • Chemokines like CXCL4 mediate antiangiogenic effects via CXCR3 receptor activation.
  • Chemokine oligomerization state influences biological function, with CXCL4 typically forming a stable tetramer.
  • The impact of CXCL4 oligomerization on receptor interaction remains unclear.

Purpose of the Study:

  • To investigate the role of CXCL4 oligomerization in its interaction with the CXCR3 receptor.
  • To determine if monomeric CXCL4 is the active form for CXCR3A binding.
  • To explore the functional implications of CXCL4 structural dynamics.

Main Methods:

  • Site-directed mutagenesis to generate CXCL4 variants with altered oligomerization states (dimers, monomers).
  • Biochemical assays to assess tetramer formation sensitivity to pH and salt concentration.
  • Receptor binding assays to evaluate the interaction of CXCL4 variants with CXCR3A.

Main Results:

  • CXCL4 tetramer formation is sensitive to pH and salt concentration, with specific residues (Glu28, Lys50) and structural elements (β-strand, C-terminal helix) being critical.
  • CXCL4 mutants were generated that exist as monomers or dimers under physiological conditions.
  • The monomeric form of CXCL4 was identified as the minimal active unit for CXCR3A interaction, with N-terminal tyrosine sulfation on the receptor being crucial for binding.
  • CXCL4L1, a variant that readily dissociates into monomers, also activates CXCR3A, supporting the role of the monomeric state.

Conclusions:

  • Monomeric CXCL4 is the active form for interacting with the CXCR3A receptor.
  • The oligomerization state of CXCL4 significantly impacts its antiangiogenic function via receptor engagement.
  • Understanding CXCL4's structural dynamics provides insights into chemokine-receptor interactions and potential therapeutic strategies.

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