Mutations in the Immunoglobulin-like Domain of gp190, the Leukemia Inhibitory Factor (LIF) Receptor, Increase or Decrease Its Affinity for LIF

The leukemia inhibitory factor (LIF) receptor comprises the low affinity binding chain gp190 and the high affinity converter gp130. The ectodomain of gp190 is among the most complex in the hematopoietin receptor family, because it contains two typical cytokine receptor homology domains separated by...

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Bibliographic Details
Published in:The Journal of biological chemistry 2003-05, Vol.278 (18), p.16253-16261
Main Authors: Bitard, Juliette, Daburon, Sophie, Duplomb, Laurence, Blanchard, Frédéric, Vuisio, Patricia, Jacques, Yannick, Godard, Anne, Heath, John K., Moreau, Jean-François, Taupin, Jean-Luc
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
Binding Sites
Cell Division
CHO Cells
COS Cells
Cricetinae
DNA-Binding Proteins
DNA-Binding Proteins - metabolism
Enzyme-Linked Immunosorbent Assay
Growth Inhibitors
Growth Inhibitors - metabolism
Humans
Immunoglobulins
Immunoglobulins - chemistry
Interleukin-6
Leukemia Inhibitory Factor
Leukemia Inhibitory Factor Receptor alpha Subunit
Life Sciences
Lymphokines
Lymphokines - metabolism
Models, Molecular
Molecular Sequence Data
Oncostatin M
Peptides
Peptides - metabolism
Phosphorylation
Point Mutation
Receptors, Cytokine
Receptors, Cytokine - chemistry
Receptors, Cytokine - metabolism
Receptors, OSM-LIF
STAT3 Transcription Factor
Structure-Activity Relationship
Surface Plasmon Resonance
Trans-Activators
Trans-Activators - metabolism
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Description
Summary:The leukemia inhibitory factor (LIF) receptor comprises the low affinity binding chain gp190 and the high affinity converter gp130. The ectodomain of gp190 is among the most complex in the hematopoietin receptor family, because it contains two typical cytokine receptor homology domains separated by an immunoglobulin-like (Ig-like) domain. Human and murine gp190 proteins share 76% homology, but murine gp190 binds human LIF with a much higher affinity, a property attributed to the Ig-like domain. Using alanine-scanning mutagenesis of the Ig-like domain, we mapped a LIF binding site at its carboxyl terminus, mainly involving residue Phe-328. Mutation of selected residues into their orthologs in the murine receptor (Q251E and N321D) significantly increased the affinity for human LIF. Interestingly, these residues, although localized at both the amino and carboxyl terminus, make a spatially unique LIF binding site in a structural model of the Ig-like module. These results demonstrate definitively the role of the Ig-like domain in LIF binding and the potential to modulate receptor affinity in this family with very limited amino acid changes.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M207193200