A novel functional epitope formed by domains 1 and 4 of the human common beta-subunit is involved in receptor activation by granulocyte macrophage colony-stimulating factor and interleukin 5.
The receptors for human interleukins 3 and 5 and granulocyte macrophage colony-stimulating factor are composed of ligand-specific alpha-subunits and a common beta-subunit (betac), the major signaling entity. The way in which betac interacts with ligands in the respective activation complexes has remained poorly understood. The recently determined crystal structure of the extracellular domain of betac revealed a possible ligand-binding interface composed of domain 1 of one chain of the betac dimer and the adjacent domain 4 of the symmetry-related chain. We have used site-directed mutagenesis, in conjunction with ligand binding and proliferation studies, to demonstrate the critical requirement of the domain 1 residues, Tyr(15) (A-B loop) and Phe(79) (E-F loop), in high affinity complex formation and receptor activation. The novel ligand-receptor interface formed between domains 1 and 4 represents the first example of a class I cytokine receptor interface to be composed of two noncontiguous fibronectin III domains.
Murphy
James M
JM
Division of Molecular Bioscience, John Curtin School of Medical Research and the Research School of Chemistry, Australian National University, Canberra, ACT 0200, Australia.
Ford
Sally C
SC
Wiedemann
Ursula M
UM
Carr
Paul D
PD
Ollis
David L
DL
Young
Ian G
IG
D000939:Epitopes; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D015848:Interleukin-5 / Q000378:metabolism / Q000494:pharmacology*; D021122:Protein Subunits; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000737:chemistry*; D018123:Receptors, Interleukin / Q000737:chemistry*; D016185:Receptors, Interleukin-3 / Q000737:chemistry*; D053649:Receptors, Interleukin-5; D013329:Structure-Activity Relationship
D000939:Epitopes; D015848:Interleukin-5; D021122:Protein Subunits; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D018123:Receptors, Interleukin; D016185:Receptors, Interleukin-3; D053649:Receptors, Interleukin-5; D016178:Granulocyte-Macrophage Colony-Stimulating Factor