Convergent mechanisms for recognition of divergent cytokines by the shared signaling receptor gp130.
Gp130 is a shared cell-surface signaling receptor for at least ten different hematopoietic cytokines, but the basis of its degenerate recognition properties is unknown. We have determined the crystal structure of human leukemia inhibitory factor (LIF) bound to the cytokine binding region (CHR) of gp130 at 2.5 A resolution. Strikingly, we find that the shared binding site on gp130 has an entirely rigid core, while the LIF binding interface diverges sharply in structure and chemistry from that of other gp130 ligands. Dissection of the LIF-gp130 interface, along with comparative studies of other gp130 cytokines, reveal that gp130 has evolved a "thermodynamic plasticity" that is relatively insensitive to ligand structure, to enable crossreactivity. These observations reveal a novel and alternative mechanism for degenerate recognition from that of structural plasticity.
Boulanger
Martin J
MJ
Department of Microbiology and Immunology, Stanford University School of Medicine, Fairchild D319, 299 Campus Drive, Stanford, CA 94305, USA.
Bankovich
Alexander J
AJ
Kortemme
Tanja
T
Baker
David
D
Garcia
K Christopher
KC
D000818:Animals; D015703:Antigens, CD / Q000737:chemistry* / Q000276:immunology; D001665:Binding Sites / Q000276:immunology; D002478:Cells, Cultured; D003429:Cross Reactions / Q000276:immunology; D018360:Crystallography, X-Ray; D050822:Cytokine Receptor gp130; D016207:Cytokines / Q000276:immunology*; D005057:Eukaryotic Cells / Q000276:immunology / Q000378:metabolism; D006131:Growth Inhibitors / Q000737:chemistry* / Q000276:immunology; D007111:Immunity, Cellular / Q000276:immunology; D007313:Insecta; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines / Q000737:chemistry* / Q000276:immunology; D046911:Macromolecular Substances; D008562:Membrane Glycoproteins / Q000737:chemistry* / Q000276:immunology; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding / Q000276:immunology; D017434:Protein Structure, Tertiary / Q000502:physiology; D011956:Receptors, Cell Surface / Q000737:chemistry* / Q000276:immunology
D015703:Antigens, CD; D016207:Cytokines; D006131:Growth Inhibitors; D015850:Interleukin-6; C507837:LIF protein, human; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines; D046911:Macromolecular Substances; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D050822:Cytokine Receptor gp130