Solution structure of eotaxin, a chemokine that selectively recruits eosinophils in allergic inflammation

Matthew P. Crump, Krishna Rajarathnam, Key Sun Kim, Ian Clark-Lewis, Brian D. Sykes

Research output: Contribution to journalArticle

85 Citations (Scopus)

Abstract

The solution structure of the CCR3-specific chemokine, eotaxin, has been determined by NMR spectroscopy. The quaternary structure of eotaxin was investigated by ultracentrifugation and NMR, and it was found to be in equilibrium between monomer and dimer under a wide range of conditions. At pH ≤ 5 and low ionic strength, eotaxin was found to be predominantly a monomer. The three-dimensional structure of the eotaxin monomer solved at pH 5.0 revealed that it has a typical chemokine fold, which includes a 3-stranded β-sheet and an overlying α-helix. Except for the N-terminal residues (residues 1-8), the core of the protein is well defined. The eotaxin structure is compared with the chemokines regulated upon activation, normal T-cell expressed and secreted (RANTES) and monocyte chemoattractant protein- 1 (MCP-1); eotaxin binds only CC chemokine receptor CCR3, whereas RANTES binds many receptors including CCR3, and MCP-1 binds a distinct receptor, CCR2. The RMSD of the eotaxin ensemble of structures with the RANTES average minimized monomeric subunit is 5.52 ± 0.87 Å over all backbone atoms and 1.14 ± 0.09 Å over backbone atoms of residues 11-28 and 34-65. The most important difference between the structures is in the N-terminal residues that are unstructured in eotaxin but structured in RANTES and MCP-1. Several residues in the loop region of RANTES show similar packing in eotaxin (residues 11-17). As the N-terminal and loop regions have been shown to be critical for receptor binding and signaling, this structure will be useful for determining the basis for CCR3 selectivity of the eotaxin.

Original languageEnglish (US)
Pages (from-to)22471-22479
Number of pages9
JournalJournal of Biological Chemistry
Volume273
Issue number35
DOIs
StatePublished - Aug 28 1998
Externally publishedYes

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T-cells
Chemokines
Eosinophils
Chemical activation
Chemokine CCL2
Inflammation
T-Lymphocytes
Monomers
CCR3 Receptors
CCR Receptors
CCR2 Receptors
Atoms
Ultracentrifugation
Ionic strength
Dimers
Osmolar Concentration
Nuclear magnetic resonance spectroscopy
Magnetic Resonance Spectroscopy
Nuclear magnetic resonance
Proteins

ASJC Scopus subject areas

  • Biochemistry

Cite this

Solution structure of eotaxin, a chemokine that selectively recruits eosinophils in allergic inflammation. / Crump, Matthew P.; Rajarathnam, Krishna; Kim, Key Sun; Clark-Lewis, Ian; Sykes, Brian D.

In: Journal of Biological Chemistry, Vol. 273, No. 35, 28.08.1998, p. 22471-22479.

Research output: Contribution to journalArticle

Crump, Matthew P. ; Rajarathnam, Krishna ; Kim, Key Sun ; Clark-Lewis, Ian ; Sykes, Brian D. / Solution structure of eotaxin, a chemokine that selectively recruits eosinophils in allergic inflammation. In: Journal of Biological Chemistry. 1998 ; Vol. 273, No. 35. pp. 22471-22479.
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abstract = "The solution structure of the CCR3-specific chemokine, eotaxin, has been determined by NMR spectroscopy. The quaternary structure of eotaxin was investigated by ultracentrifugation and NMR, and it was found to be in equilibrium between monomer and dimer under a wide range of conditions. At pH ≤ 5 and low ionic strength, eotaxin was found to be predominantly a monomer. The three-dimensional structure of the eotaxin monomer solved at pH 5.0 revealed that it has a typical chemokine fold, which includes a 3-stranded β-sheet and an overlying α-helix. Except for the N-terminal residues (residues 1-8), the core of the protein is well defined. The eotaxin structure is compared with the chemokines regulated upon activation, normal T-cell expressed and secreted (RANTES) and monocyte chemoattractant protein- 1 (MCP-1); eotaxin binds only CC chemokine receptor CCR3, whereas RANTES binds many receptors including CCR3, and MCP-1 binds a distinct receptor, CCR2. The RMSD of the eotaxin ensemble of structures with the RANTES average minimized monomeric subunit is 5.52 ± 0.87 {\AA} over all backbone atoms and 1.14 ± 0.09 {\AA} over backbone atoms of residues 11-28 and 34-65. The most important difference between the structures is in the N-terminal residues that are unstructured in eotaxin but structured in RANTES and MCP-1. Several residues in the loop region of RANTES show similar packing in eotaxin (residues 11-17). As the N-terminal and loop regions have been shown to be critical for receptor binding and signaling, this structure will be useful for determining the basis for CCR3 selectivity of the eotaxin.",
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