LIF receptor-gp130 interaction investigated by homology modeling: implications for LIF binding.
Leukemia inhibitory factor (LIF), a member of the gp130 family of helical cytokines, is involved in the hemopoietic and neural systems. The LIF signal transducing complex contains two receptor molecules, the LIF receptor (LIFR) and gp130. The extracellular region of the LIFR is unique in that it includes three membrane-proximal fibronectin type III domains and two cytokine binding domains (CBDs) separated by an immunoglobulin-like domain. Although some mutagenesis data on LIF are available, it is not yet known which regions of LIFR or gp130 bind LIF. Nor is it known whether LIFR contacts gp130 in a manner similar to the growth hormone receptor dimer and, if so, through which of its CBDs. To attempt to elucidate these matters and to investigate the receptor complex, models of the CBDs of LIFR and the CBD of gp130 were constructed. Analyses of the electrostatic isopotential surfaces of the CBD models suggest that gp130 and the membrane-proximal CBD of LIFR hetero-dimerize and bind LIF through contacts similar to those seen in the growth hormone receptor dimer. This work further demonstrates the utility of electrostatic analyses of homology models and suggests a strategy for biochemical investigations of the LIF-receptor complex.
Smith
D K
DK
Ludwig Institute for Cancer Research, Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, Australia.
Treutlein
H R
HR
D000595:Amino Acid Sequence; D015703:Antigens, CD / Q000737:chemistry*; D001665:Binding Sites / Q000502:physiology; D003198:Computer Simulation; D050822:Cytokine Receptor gp130; D019281:Dimerization; D006131:Growth Inhibitors; D006801:Humans; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; D008222:Lymphokines; D008562:Membrane Glycoproteins / Q000737:chemistry*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding / Q000502:physiology; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D018121:Receptors, Cytokine / Q000737:chemistry*; D053606:Receptors, OSM-LIF; D011986:Receptors, Somatotropin / Q000737:chemistry; D016415:Sequence Alignment; D015398:Signal Transduction / Q000502:physiology; D055672:Static Electricity
D015703:Antigens, CD; D006131:Growth Inhibitors; C494199:IL6ST protein, human; D015850:Interleukin-6; C507837:LIF protein, human; C507840:LIFR protein, human; D053605:Leukemia Inhibitory Factor; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; D008222:Lymphokines; D008562:Membrane Glycoproteins; D018121:Receptors, Cytokine; D053606:Receptors, OSM-LIF; D011986:Receptors, Somatotropin; D050822:Cytokine Receptor gp130