TI  - Influence of   <prot>interleukin-6</prot> (<prot>IL-6</prot>)   dimerization on formation of the high
      affinity hexameric <prot><prot>IL-6</prot>.receptor</prot> complex.
PG  - 20138-44
AB  - The high affinity <prot>interleukin-6</prot> (<prot>IL-6</prot>) signaling complex consists of  <prot>IL-6</prot> 
      and two membrane-associated receptor components: a low affinity but
      specific  <prot><prot>IL-6</prot> receptor</prot>  and the affinity converter/signal transducing
      protein  <prot>gp130</prot> . Monomeric (<prot>IL-6M</prot>) and dimeric (  <prot>IL-6D</prot>  ) forms of Escherichia
      coli-derived human <prot>IL-6</prot> and the extracellular (&quot;soluble&quot;) portions of the
      <prot><prot>IL-6</prot> receptor</prot> (<prot>sIL-6R</prot>) and <prot>gp130</prot> have been purified in order to
      investigate the effect of   <prot>IL-6</prot>   dimerization on binding to the receptor
      complex. Although  <prot>IL-6D</prot>  has a higher binding affinity for immobilized
       <prot>sIL-6R</prot>,  as determined by biosensor analysis employing surface plasmon
      resonance detection, <prot>IL-6M</prot> is more potent than <prot>IL-6D</prot> in a STAT3
      phosphorylation assay. The difference in potency is significantly less
      pronounced when measured in the murine 7TD1 hybridoma growth factor assay
      and the human hepatoma HepG2 bioassay due to time-dependent dissociation
      at 37 ?C of   <prot>IL-6</prot>   dimers into active monomers. The increased binding
      affinity of  <prot>IL-6D</prot>  appears to be due to its ability to cross-link two
       <prot>sIL-6R</prot>  molecules on the biosensor surface. Studies of the <prot>IL-6</prot> ternary
      complex formation demonstrated that the reduced biological potency of
      <prot>IL-6D</prot> resulted from a decreased ability of the   <prot>IL-6D</prot>   (<prot>sIL-6R</prot>) 2  complex to
      couple with the soluble portion of  <prot>gp130</prot> . These data imply that
       <prot>IL-6</prot> -induced dimerization of  <prot>sIL-6R</prot>  is not the driving force in promoting
      formation of the hexameric (<prot>IL-6</prot> <prot>IL-6R</prot> <prot>gp130</prot>)2 complex. A model is
      presented whereby the trimeric complex of  <prot>IL-6R</prot> ,  <prot>gp130</prot> , and  <prot>IL-6M</prot>  forms
      before the functional hexamer. Due to its increased affinity for the  <prot>IL-6R</prot>
      but its decreased ability to couple with  <prot>gp130</prot> , we suggest that a stable
        <prot>IL-6</prot>   dimer may be an efficient <prot>IL-6</prot> antagonist.
AD  - Joint Protein Structure Laboratory, Ludwig Institute for Cancer Research
