The unusual species cross-reactivity of the leukemia inhibitory factor receptor alpha-chain is determined primarily by the immunoglobulin-like domain
- Author(s)
- Owczarek, CM; Zhang, Y; Layton, MJ; Metcalf, D; Roberts, B; Nicola, NA;
- Details
- Publication Year 1997-09-19,Volume 272,Issue #38,Page 23976-23985
- Journal Title
- JOURNAL OF BIOLOGICAL CHEMISTRY
- Publication Type
- Journal Article
- Abstract
- Human leukemia inhibitory factor (hLIF) binds to both human and mouse LIF receptors (LIFRs), while mouse LIF (mLIF) binds only to mouse LIFRs. Furthermore, hLIF binds with much higher affinity to the mouse LIFR (mLIFR) alpha-chain than does mLIF itself. To define the structural elements of the mLIFR alpha-chain conferring high affinity binding of hLIF and the species-specific interaction with mLIF, we first constructed C-terminally truncated extracellular domains of both the mLIFR and the human LIFR (hLIFR) alpha-chains, which contained only the two hemopoietin domains separated by an immunoglobulin-like domain. These recombinant truncated LIFR alpha-chains had identical binding and biological characteristics to either their naturally occurring or transfected counterparts. On the basis of this, we have generated eight interspecies receptor chimeras by combining different regions of the mouse and human LIFR sequence. Surprisingly, the immunoglobulin-like domain of the mLIFR, alpha-chain played the predominant role in receptor-ligand interactions. Moreover, both high affinity binding for hLIF and the species-specific binding for mLIF mapped to the same domain of mLIFR molecule, These findings should enable the development of a ''humanized'' mouse LIFR that could act as a potent antagonist of hLIF biological activities in vivo.
- Publisher
- AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
- Keywords
- COLONY-STIMULATING FACTOR; IL-6 SIGNAL TRANSDUCER; MOLECULAR-CLONING; EXPRESSION CLONING; HUMAN HOMOLOG; GENE FAMILY; BINDING; MURINE; GP130; COMPLEX
- Publisher's Version
- https://doi.org/10.1074/jbc.272.38.23976
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 1997-09-19 12:00:00