Proper functioning of the immune system depends on the ability of cells to interact with each other. These interactions can occur in two possible ways. The first is by direct cell-to-cell contact. This implicates cell-surface proteins in the interaction, probably as ligand-receptor pairs. The second is by the exchange of protein mediators known as cytokines. These are small proteins that are highly mobile and can be rapidly transported to distant sites. The cytokines then interact with specific receptors or subsets of receptors on target cells. Many cytokines are also known to be able to form concentration gradients, and are therefore thought to be important controllers of directed cell migration.
A large number of cytokines are now known, and a substantial amount is known about many of them. They can be subdivided into a variety of superfamilies. One of the largest and best studied of these is a superfamily of proteins known as the Chemokines. All the members of this superfamily have molecular weights in the 8-10 kDa range and are heparin-binding polypeptides. As shown below, the chemokines can be further subdivided into two families, depending on the distribution of cysteine residues in the proteins. The 'CXC' family have a single residue between the first 2 cysteines of the sequence, whereas in the 'CC' family the first two cysteines in the sequence are adjacent. In addition, genes encoding for members of the CXC family are found to be clustered on the q12-21 region of human chromosome 4, and the genes encoding members of the CC family are found on the q11-21 region of human chromosome 17.
(Click on any of the highlighted proteins for its structure.)
Four CXC Chemokine structures have been solved to date: bovine Platelet Factor 4, recombinant human Platelet Factor 4 and Interleukin-8 crystal structures have all been solved. The nmr structures of Interleukin-8 and Melanoma Growth Stimulatory Activity (or gro) are also known. All four molecules have the same monomer structure, but IL-8 and MGSA exist as dimers and hPF4 and bPF4 as tetramers under physiological conditions. All of the CXCs are thought to have the same monomer structure, which can then combine to form dimers or tetramers.
(Click on any of the highlighted proteins for its structure.)
Only one CC Chemokine structure is known; the NMR structure of MIP-1b was published recently. It has the same monomer as the CXC Chemokines, but was surprisingly found to dimerise in a different way to those proteins. It now seems likely that all the CC Chemokines also have the same monomer structure but form dimers and perhaps tetramers in different ways to the CXCs.
John Maclean johnm@chem.gla.ac.uk