Structural biology of shared cytokine receptors.
Recent structural information for complexes of cytokine receptor ectodomains bound to their ligands has significantly expanded our understanding of the macromolecular topology and ligand recognition mechanisms used by our three principal shared cytokine signaling receptors-gp130, gamma(c), and beta(c). The gp130 family receptors intricately coordinate three structurally unique cytokine-binding sites on their four-helix bundle cytokine ligands to assemble multimeric signaling complexes. These organizing principles serve as topological blueprints for the entire gp130 family of cytokines. Novel structures of gamma(c) and beta(c) complexes show us new twists, such as the use of a nonstandard sushi-type alpha receptors for IL-2 and IL-15 in assembling quaternary gamma(c) signaling complexes and an antiparallel interlocked dimer in the GM-CSF signaling complex with beta(c). Unlike gp130, which appears to recognize vastly different cytokine surfaces in chemically unique fashions for each ligand, the gamma(c)-dependent cytokines appear to seek out some semblance of a knobs-in-holes shape recognition code in order to engage gamma(c) in related fashions. We discuss the structural similarities and differences between these three shared cytokine receptors, as well as the implications for transmembrane signaling.
Wang
Xinquan
X
Howard Hughes Medical Institute, Stanford University School of Medicine, Departments of Molecular and Cellular Physiology, and Structural Biology, Stanford, California 94305, USA. wxq@stanford.edu
Lupardus
Patrick
P
Laporte
Sherry L
SL
Garcia
K Christopher
KC
D000818:Animals; D001665:Binding Sites; D053648:Cytokine Receptor Common beta Subunit / Q000737:chemistry / Q000378:metabolism; D050822:Cytokine Receptor gp130 / Q000737:chemistry* / Q000378:metabolism*; D016207:Cytokines / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D053631:Interleukin Receptor Common gamma Subunit / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D011485:Protein Binding; D011487:Protein Conformation; D015398:Signal Transduction
D053648:Cytokine Receptor Common beta Subunit; D016207:Cytokines; D053631:Interleukin Receptor Common gamma Subunit; D008024:Ligands; D050822:Cytokine Receptor gp130