The solution structure of the cytokine-binding domain of the common beta-chain of the receptors for granulocyte-macrophage colony-stimulating factor,interleukin-3 and interleukin-5

The haemopoietic cytokines, granulocyte-macrophage colony-stimulating facto r, interleukin-3 and interleukin-5 bind to cell-surface receptors comprisin g ligand-specific a-chains and a shared beta-chain. The beta-chain is the c ritical signalling subunit of the receptor and its fourth domain not only p lays a critical role in interactions with ligands, hence in receptor activa tion, but also contains residues whose mutation can lead to ligand-independ ent activation of the receptor. We have determined the NMR solution structu re of the isolated human fourth domain of the beta-chain. The protein has a fibronectin type III fold with a well-defined hydrophobic core and is stab ilised by an extensive network of pi-cation interactions involving Trp and Arg side-chains, including two Trp residues outside the highly conserved Tr p-Ser-Xaa-Trp-Ser motif (where Xaa is any amino acid) that is found in many cytokine receptors. Most of the residues implicated in factor-independent mutants localise to the rigid core of the domain or the pi-cation stack. Th e loops between the B and C, and the F and G strands, that contain residues important for interactions with cytokines, lie adjacent at the membrane-di stal end of the domain, consistent with their being involved cooperatively in binding cytokines. The elucidation of the structure of the cytokine-bind ing domain of the beta-chain provides insight into the cytokine-dependent a nd factor-independent activation of the receptor. (C) 2000 Academic Press.