Solution Structure of the Human CC Chemokine 2:  A Monomeric Representative of the CC Chemokine Subtype^,

Abstract

HCC-2, a 66-amino acid residue human CC chemokine, was reported to induce chemotaxis on monocytes, T-lymphocytes, and eosinophils. The three-dimensional structure of HCC-2 has been determined by 1 H nuclear magnetic resonance (NMR) spectroscopy and restrained molecular dynamics calculations on the basis of 871 experimental restraints. The structure is well-defined, exhibiting average root-mean-square deviations of 0.58 and 0.96 Å for the backbone heavy atoms and all heavy atoms of residues 5-63, respectively. In contrast to most other chemokines, subtle structural differences impede dimer formation of HCC-2 in a concentration range of 0.1 µM to 2 mM. HCC-2, however, exhibits the same structural elements as the other chemokines, i.e., a triple-stranded antiparallel -sheet covered by an R-helix, showing that the chemokine fold is not influenced by quaternary interactions. Structural investigations with a HCC-2 mutant prove that a third additional disulfide bond present in wild-type HCC-2 is not necessary for maintaining the relative orientation of the helix and the -sheet.

Structure-Function Analysis of CCL28 in the Development of Post-viral Asthma

“…For human CCL15 and CCL23, chemokines that share ϳ64% identity, the extra disulfide seems to have a negligible effect on structure. The extra disulfide in these two chemokines links a 3 10 -helical turn just before the first ␤-strand to the C-terminal ␣-helix and does not disrupt the conserved chemokine fold (17,19). In addition, mutational studies with CCL15 have shown that disruption of the extra disulfide has a minimal effect on protein structure (17).…”

“…The extra disulfide in these two chemokines links a 3 10 -helical turn just before the first ␤-strand to the C-terminal ␣-helix and does not disrupt the conserved chemokine fold (17,19). In addition, mutational studies with CCL15 have shown that disruption of the extra disulfide has a minimal effect on protein structure (17). However, structural studies on the chemokine CCL1 have shown that its extra disulfide bond significantly affects the conserved chemokine fold, resulting in disruption of the C-terminal ␣-helix and the formation of a short extended C-terminal strand not seen in other chemokines (16).…”

Molecular determinants for CC-chemokine recognition by a poxvirus CC-chemokine inhibitor

“…Many chemokines form homodimers or oligomers at high nanomolar to micromolar concentrations (36-39) whereas others exist strictly as monomers (40)(41)(42)(43)(44). For IL-8, MCP-1, MCP-2, and I-309, the monomeric form predominates in solution at physiological (nM) concentrations (32,44,45).…”

Receptor-binding conformation of the ?ELR? motif of IL-8: X-ray structure of the L5C/H33C variant at 2.35 ? resolution

“…The various structurally characterized members of the family differ in their extent of oligomerization (monomers, dimers, and tetramers) and/or the surface used for the oligomerization interaction. [2][3][4] All the monomers, however, have a three-stranded ␤-sheet, followed by an ␣-helix and preceded by an extended N-terminal segment of approximately 20 amino acids. Four subclasses are currently discriminated on the basis of their pattern of cysteines near their N-terminus.…”