Analysis of hydrophobicity in the alpha and beta chemokine families and its relevance to dimerization.
The chemokine family of chemotactic cytokines plays a key role in orchestrating the immune response. The family has been divided into 2 subfamilies, alpha and beta, based on the spacing of the first 2 cysteine residues, function, and chromosomal location. Members within each subfamily have 25-70% sequence identity, whereas the amino acid identity between members of the 2 subfamilies ranges from 20 to 40%. A quantitative analysis of the hydrophobic properties of 11 alpha and 9 beta chemokine sequences, based on the coordinates of the prototypic alpha and beta chemokines, interleukin-8 (IL-8), and human macrophage inflammatory protein-1 beta (hMIP-1 beta), respectively, is presented. The monomers of the alpha and beta chemokines have their strongest core hydrophobic cluster at equivalent positions, consistent with their similar tertiary structures. In contrast, the pattern of monomer surface hydrophobicity between the alpha and beta chemokines differs in a manner that is fully consistent with the observed differences in quaternary structure. The most hydrophobic surface clusters on the monomer subunits are located in very different regions of the alpha and beta chemokines and comprise in each case the amino acids that are buried at the interface of their respective dimers. The theoretical analysis of hydrophobicity strongly supports the hypothesis that the distinct dimers observed for IL-8 and hMIP-1 beta are preserved for all the alpha and beta chemokines, respectively. This provides a rational explanation for the lack of receptor crossbinding and reactivity between the alpha and beta chemokine subfamilies.
Covell
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DG
Biomedical Supercomputing Laboratory, PRI/Dyncorp, Frederick Cancer Research and Development Center, National Cancer Institute, Maryland 21702.
Smythers
G W
GW
Gronenborn
A M
AM
Clore
G M
GM
D000595:Amino Acid Sequence; D054407:Chemokine CCL4; D016207:Cytokines / Q000737:chemistry*; D016209:Interleukin-8 / Q000737:chemistry*; D008024:Ligands; D019402:Macrophage Inflammatory Proteins; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015846:Monokines / Q000737:chemistry*; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D017421:Sequence Analysis; D017386:Sequence Homology, Amino Acid
D054407:Chemokine CCL4; D016207:Cytokines; D016209:Interleukin-8; D008024:Ligands; D019402:Macrophage Inflammatory Proteins; D015846:Monokines