Three‐dimensional structures of α and β chemokines

Members of the chemokine family of proteins play a key role in the orchestration of the immune response. This family has been further divided into two subfamilies, α and β, based on sequence, function, and chromosomal location. To date, the three‐dimensional structures of two members of the α subfamily, interleukin‐8 (IL‐8) and platelet factor 4, and one member of the β subfamily, human macrophage inflammatory protein‐1β (hMIP‐1β), have been solved by either NMR or X‐ray crystallography. In this review, we discuss their three‐dimensional structures and their possible relationship to function. The structures of the monomers are very similar, as expected from the significant degree of sequence identity between these proteins. The quaternary structures of the α and β chemokines, however, are entirely distinct and the dimer interface is formed by a completely different set of residues. Whereas the IL‐8 dimer is globular, the hMIP‐1β dimer is elongated and cylindrical. Platelet factor 4 is a tetramer comprising a dimer of dimers of the IL‐8 type. The IL‐8 dimer comprises a six stranded anti‐parallel β‐sheet, three strands contributed by each subunit, on top of which lie two anti‐parallel helices separated by approximately 14 A, and the symmetry axis is located between residues 26 and 26' (equivalent to residue 29 of hMIP‐1β) at the center of strands β, and β 1 '. In contrast, in the hMIP‐1β dimer the symmetry axis is located between residues 10 and 10' which are part of an additional mini‐antiparallel β‐sheet formed by strands β 0 and β 0 '; the two helices are 46 Å apart on opposite sides of the molecule; and strands β 1 and β 1 ' are about 30 Å apart and located on the exterior of the protein. Calculation of the solvation free energies of dimerization and analysis of hydrophobic clusters strongly suggests that the formation and stabilization of the two different types of dimers arise from the burial of hydrophobic residues, and that the distinct quaternary structures are preserved throughout the two subfamilies, The implications with regard to receptor recognition and the absence of cross‐binding between the two subfamilies are discussed.—Clore, G. M., Gronenborn, A. M. Three‐dimensional structures of a and β chemokines. FASEB J. 9, 57‐62 (1995)