Conservation of functional sites on interleukin-6 and implications for evolution of signaling complex assembly and therapeutic intervention.
J Biol Chem
; 287(47): 40043-50, 2012 Nov 16.
Article
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| MEDLINE
| ID: mdl-23027872
ABSTRACT
A number of secreted cytokines, such as interleukin-6 (IL-6), are attractive targets for the treatment of inflammatory diseases. We have determined the solution structure of mouse IL-6 to assess the functional significance of apparent differences in the receptor interaction sites (IL-6Rα and gp130) suggested by the fairly low degree of sequence similarity with human IL-6. Structure-based sequence alignment of mouse IL-6 and human IL-6 revealed surprising differences in the conservation of the two distinct gp130 binding sites (IIa and IIIa), which suggests a primacy for site III-mediated interactions in driving initial assembly of the IL-6/IL-6Rα/gp130 ternary complex. This is further supported by a series of direct binding experiments, which clearly demonstrate a high affinity IL-6/IL-6Rα-gp130 interaction via site III but only weak binding via site II. Collectively, our findings suggest a pathway for the evolution of the hexameric, IL-6/IL-6Rα/gp130 signaling complex and strategies for therapeutic targeting. We propose that the signaling complex originally involved specific interactions between IL-6 and IL-6Rα (site I) and between the D1 domain of gp130 and IL-6/IL-6Rα (site III), with the later inclusion of interactions between the D2 and D3 domains of gp130 and IL-6/IL-6Rα (site II) through serendipity. It seems likely that IL-6 signaling benefited from the evolution of a multipurpose, nonspecific protein interaction surface on gp130, now known as the cytokine binding homology region (site II contact surface), which fortuitously contributes to stabilization of the IL-6/IL-6Rα/gp130 signaling complex.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Interleucina-6
/
Evolución Molecular
/
Receptores de Interleucina-6
/
Complejos Multiproteicos
/
Receptor gp130 de Citocinas
Límite:
Animals
/
Humans
Idioma:
En
Revista:
J Biol Chem
Año:
2012
Tipo del documento:
Article
País de afiliación:
Reino Unido