The crystal structure and biological function of leukemia inhibitory factor: implications for receptor binding.
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.
Department of Biochemistry, University of Oxford, England.
R C
RC
Robinson
L M
LM
Grey
D
D
Staunton
H
H
Vankelecom
A B
AB
Vernallis
J F
JF
Moreau
D I
DI
Stuart
J K
JK
Heath
E Y
EY
Jones
D000595:Amino Acid Sequence; D000818:Animals; D018360:Crystallography, X-Ray; D006131:Growth Inhibitors / Q000378:metabolism*; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; D008024:Ligands; D008222:Lymphokines / Q000378:metabolism* / Q000648:ultrastructure*; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D018121:Receptors, Cytokine / Q000378:metabolism; D053606:Receptors, OSM-LIF; D011993:Recombinant Fusion Proteins / Q000737:chemistry; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
D006131:Growth Inhibitors; D015850:Interleukin-6; C507837:LIF protein, human; C507840:LIFR protein, human; D053605:Leukemia Inhibitory Factor; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; C507838:Lif protein, mouse; C507841:Lifr protein, mouse; D008024:Ligands; D008222:Lymphokines; D018121:Receptors, Cytokine; D053606:Receptors, OSM-LIF; D011993:Recombinant Fusion Proteins