TI  - Localization of functional receptor epitopes on the structure of ciliary
      neurotrophic factor indicates a conserved, function-related epitope
      topography among helical cytokines.
PG  - 14007-14
AB  - By rational mutagenesis, receptor-specific functional analysis, and
      visualization of complex formation in solution, we identified individual
      amino acid side chains involved specifically in the interaction of  <prot>ciliary
      neurotrophic factor</prot> (<prot>CNTF</prot>)  with  <prot>CNTFR alpha</prot>  and not with the
      beta-components, <prot>gp130</prot> and <prot>LIFR</prot>. In the crystal structure, the side chains
      of these residues, which are located in helix A, the AB loop, helix B, and
      helix D, are surface accessible and are clustered in space, thus
      constituting an epitope for <prot>CNTFR alpha</prot>. By the same analysis, a partial
      epitope for <prot>gp130</prot> was also identified on the surface of helix A that faces
      away from the alpha-epitope. Superposition of the <prot>CNTF</prot> and growth hormone
      structures showed that the location of these epitopes on <prot>CNTF</prot> is analogous
      to the location of the first and second receptor epitopes on the surface
      of growth hormone. Further comparison with proposed binding sites for
      alpha- and beta-receptors on <prot>interleukin-6</prot> and leukemia inhibitory factor
      indicated that this epitope topology is conserved among helical cytokines.
      In each case, epitope I is utilized by the specificity-conferring
      component, whereas epitopes II and III are used by accessory components.
      Thus, in addition to a common fold, helical cytokines share a conserved
      order of receptor epitopes that is function related.
AD  - REGENERON Pharmaceuticals Inc., Tarrytown, New York 10591-6707, USA.
