The crystal structure and biological function of leukemia inhibitory factor: implications for receptor binding

• Published in: Cell Vol. 77; no. 7; p. 1101
• Main Authors: Robinson, R C, Grey, L M, Staunton, D, Vankelecom, H, Vernallis, A B, Moreau, J F, Stuart, D I, Heath, J K, Jones, E Y
• Format: Journal Article
• Language: English
• Published: United States 01-07-1994
• Subjects: Amino Acid Sequence; Animals; Crystallography, X-Ray; Growth Inhibitors - metabolism; Interleukin-6; Leukemia Inhibitory Factor; Leukemia Inhibitory Factor Receptor alpha Subunit; Ligands; Lymphokines - metabolism; Lymphokines - ultrastructure; Mice; Models, Molecular; Molecular Sequence Data; Protein Structure, Tertiary; Receptors, Cytokine - metabolism; Receptors, OSM-LIF; Recombinant Fusion Proteins - chemistry; Sequence Alignment; Sequence Homology, Amino Acid
• ISSN: 0092-8674
• DOI: 10.1016/0092-8674(94)90449-9

The structure of murine leukemia inhibitory factor (LIF) has been determined by X-ray crystallography at 2.0 A resolution. The main chain fold conforms to the four alpha-helix bundle topology previously observed for several members of the hematopoietic cytokine family. Of these, LIF shows closest structural homology to granulocyte colony-stimulating factor and growth hormone (GH). Sequence alignments for the functionally related molecules oncostatin M and ciliary neurotrophic factor, when mapped to the LIF structure, indicate regions of conserved surface character. Analysis of the biological function and receptor specificity of a series of human-mouse LIF chimeras implicate two regions of receptor interaction that are located in the fourth helix and the preceding loop. A model for receptor binding based on the structure of the GH ligand-receptor complex requires additional, novel features to account for these data.