Modeling the three–dimensional structure of the monocyte chemo–attractant and activating protein MCAF/MCP-1 on the basis of the solution structure of interleukin-8

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Abstract
A model of the three-dimensional structure of the monocyte chemo-attractant and activating protein MCAF/MCP-1 is presented. The model is predicted based on the previously determined solution structure of interleukin-8 (IL-8/NAP-1) [Clore,G.M., Appella,E., Yamada,M., Matsushima,K. and Gronenborn,A.M. (1990) Biochemistry 29, 1689-1696]. Both proteins belong to a superfamily of cytokine proteins involved in cell-specific chemotaxis, host defense and the inflammatory response. The amino acid sequence identity between the two proteins is 24%. It is shown that the regular secondary structure elements of the parent structure can be retained in the modeled structure, such that the backbone hydrogen bonding pattern is very similar in the two structures. The polypeptide backbone is superimposable with an atomic r.m.s. difference of 0.9 angstrom and all side chains can be modelled by transferring the parent side chain conformation to the new structure. Thus, the deduced structure, like the parent one, is a dimer and consists of a six-stranded antiparallel beta-sheet, formed by two three-stranded Greek keys, one from each monomer, upon which lie two symmetry-related antiparallel alpha-helices, approximately 24 angstrom long and separated by approximately 14 angstrom. All amino acid sequence changes can be accommodated within the parent polypeptide framework without major rearrangements. This is borne out by the fact that the IL-8/NAP-1 and modeled MCAF/MCP-1 structures have similar non-bonding energies. These results strongly suggest that both proteins and all other members of the superfamily most likely have the same tertiary structure. Analysis of the distribution of the solvent-exposed residues can be interpreted in the context of the different receptors involved in mediating the specific responses to both proteins and suggests that the different activities of the two proteins, namely neutrophil (IL-8) versus monocyte (MCAF/MCP-1) activation and chemotaxis, reside in the specific arrangements of amino acid side chains pointing outwards from and lying in the cleft between the two exposed long alpha-helices.

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