Cell
Volume 77, Issue 7, 1 July 1994, Pages 1101-1116
Journal home page for Cell

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

https://doi.org/10.1016/0092-8674(94)90449-9Get rights and content

Abstract

The structure of murine leukemia inhibitory factor (LIF) has been determined by X-ray crystallography at 2.0 Å resolution. The main chain fold conforms to the four α-helix bundle topology previously observed for several members of the hematopoletic 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.

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      This phosphorylation process results in the activation of several signaling pathways (Fig. 1), namely: (i) phosphorylation of signal transducers, STAT, that homodimerize and translocate to the nucleus, binding to DNA; (ii) activation of phosphoinositide-3-Kinase (PI3K) pathway; and (iii) mitogen-activated protein kinase kinase / extracellular signal-regulated kinase (MEK/ERK) pathway. Regarding its structure and phylogeny, LIF is characterized by a four α-helix bundle topology stabilized by three disulfide bridges, highly conserved between mouse and humans [19,20]. This conserved topology is important for the known cross-reactivity of human and murine LIFs – human LIF is active in both human and murine LIFRs, although murine LIF is only capable of eliciting the receptor of the same species [21,22].

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