Elucidating the structural mechanisms for biological activity of the chemokine family.

Chemokines are a family of proteins involved in inflammatory and immune response. They share a common fold, made up of a three-stranded beta-sheet, and an overlaying alpha-helix. Chemokines are mainly categorized into two subfamilies distinguished by the presence or absence of a residue between two conserved cysteines in the N-terminus. Although dimers and higher-order quaternary structures are common in chemokines, they are known to function as monomers. Yet, there is quite a bit of controversy on how the actual function takes place. The mechanisms of binding and activation in the chemokine family are investigated using the gaussian network model of proteins, a low-resolution model that monitors the collective motions in proteins. It is particularly suitable for elucidating the global dynamic characteristics of large proteins or the common properties of a group of related proteins such as the chemokine family presently investigated. A sample of 16 proteins that belong to the CC, CXC, or CX(3)C subfamilies are inspected. Local packing density and packing order of residues are used to determine the type and range of motions on a global scale, such as those occurring between various loop regions. The 30s-loop, although not directly involved in the binding interface like the N-terminus and the N-loop, is identified as having a prominent role in both binding/activation and dimerization. Two mechanisms are distinguished based on the communication among the three flexible regions. In these two-step mechanisms, the 30s-loop assists either the N-loop or the N-terminus during binding and activation. The findings are verified by molecular mechanics and molecular dynamics simulations carried out on the detailed structure of representative proteins from each mechanism type. A basis for the construction of hybrids of chemokines to bind and/or activate various chemokine receptors is presented. Proteins 2001;43:150-160. Copyright 2001 Wiley-Liss, Inc.