ANALYSIS OF HYDROPHOBICITY IN THE ALPHA-CHEMOKINE AND BETA-CHEMOKINE FAMILIES AND ITS RELEVANCE TO DIMERIZATION

The chemokine family of chemotactic cytokines plays a key role in orch estrating the immune response. The family has been divided into 2 subf amilies, alpha and beta, based on the spacing of the first 2 cysteine residues, function, and chromosomal location. Members within each subf amily have 25-70% sequence identity, whereas the amino acid identity b etween members of the 2 subfamilies ranges from 20 to 40%. A quantitat ive analysis of the hydrophobic properties of 11 alpha and 9 beta chem okine sequences, based on the coordinates of the prototypic alpha and beta chemokines, interleukin-8 (IL-8), and human macrophage inflammato ry protein-1 beta (hMIP-1 beta), respectively, is presented. The monom ers of the alpha and beta chemokines have their strongest core hydroph obic cluster at equivalent positions, consistent with their similar te rtiary structures. In contrast, the pattern of monomer surface hydroph obicity between the alpha and beta chemokines differs in a manner that is fully consistent with the observed differences in quaternary struc ture. The most hydrophobic surface clusters on the monomer subunits ar e located in very different regions of the alpha and beta chemokines a nd comprise in each case the amino acids that are buried at the interf ace of their respective dimers. The theoretical analysis of hydrophobi city strongly supports the hypothesis that the distinct dimers observe d for IL-8 and hMIP-1 beta are preserved for all the alpha and beta ch emokines, respectively. This provides a rational explanation for the l ack of receptor crossbinding and reactivity between the alpha and beta chemokine subfamilies.