Nature's Design for a Versatile Interaction Domain

STKE  30 Sep 2003:
Vol. 2003, Issue 202, pp. tw376-TW376
DOI: 10.1126/stke.2003.202.tw376

The gp130 protein is a shared receptor subunit that binds to at least 10 different cytokines. Boulanger et al. were therefore curious what features of gp130 would allow interaction with such a range of structurally dissimilar cytokines. Comparison of various cytokine-gp130 crystal structures showed that in fact the interactions predominantly occur through a single region of gp130. Furthermore, a crystal structure of the cytokine leukemia inhibitory factor (LIF) with the cytokine binding region of gp130 showed this region of the gp130 protein to be unusually rigid. Thus, the authors argue that gp130 is unlikely to accommodate its multiple ligands through conformational changes. Further analysis of the interaction by computational alanine scanning mutagenesis and thermodynamic measurements made by isothermal titration calorimetry support what the authors call a "thermodynamic plasticity" of the interaction site. Depending on the nature of the ligand, the interaction site of gp130 offers either polar interactions or hydrophobic interactions that favor binding in a manner that is relatively insensitive to ligand structure. Release of bound water molecules appears to contribute favorable gain in entropy to the binding reactions. Some gp130-interacting cytokines interact through another domain with a separate α-receptor subunit. In this case, the interaction mechanism is very different: It is sensitive to ligand structure and entropically unfavorable, relying primarily on hydrogen bonds and salt bridges. The authors note that the gp130 system offers a potential therapeutic target for a large range of physiological processes, and better understanding of its multiple interactions may allow strategies that specifically alter a particular action of this multifaceted signaling molecule.

M. J. Boulanger, A. J. Bankovich, T. Kortemme, D. Baker, K. C. Garcia, Convergent mechanisms for recognition of divergent cytokines by the shared signaling receptor gp130. Mol. Cell 12, 577-589 (2003). [Online Journal]