GM-CSF/GM-CSF receptor complex
Cytokines are group of small proteins that serve as intercellular signal transduction. (Refer to Figure.1). The main roles of these proteins is to meditate immunity system and regulate cell proliferation, differentiation and activation. For instance, please refer to Interleukin-1 beta(PDB:1I1B) and Interleukin-18(PDB:1J0S). The cytokines, which are produced and released from one cell, transmit information to the target cells by activating the cytokine receptors exist on the surface of them. Basically, cytokine receptor is composed of several separated subunits. The cytokine-binding induces them to assemble into a active complex. Then, the active complex prompts various target cell responses through sending signals to the cell interior.
The GM-CSF(Granulocyte-macrophage colony-stimulating factor), Interleukin-3(IL-3), and Interleukin-5(IL-5) family of cytokines have important roles of regulating the production, proliferation, and functional activation of hematopoietic cells. The defect in such regulatory system is leads to disease such as leukemia or rheumatoid arthritis. As a common feature of the three types of the cytokines, the receptor of them consists of two subunits: a alpha and a beta subunit. It has been known that the two subunits assemble into a activated heterodimer through the cytokine-binding. However, the detailed mechanism about the dimerization, activation and signalization remain unclear. The crystal structure of GM-CSF and GM-CSF receptor complex provided important insight into the mechanism.
The structure of the GM-CSF/GM-CSF receptor complex reveals a 2:2:2 hexamer consisting of two GM-CSF molecules, two GMRa chains, and two Bc chains. (Refer to Figure.2).
In the three main interfaces, the important inter-residue interactions which contribute to the structural stability of the hexamer complex are shown in below. (Refer to Figure.3).
Furthermore, the authors suggested that the two hexamer complexes need to assemble into a high-order dodecamer complex, to express the function as intracellular signaling. This suggestion is based on two bases as show in below.
In summary, the activation and functional expression mechanism of GM-CSF receptor consists of two steps, where the hexamer complex provides for high-affinity cytokine binding but the dodecamer complex is required for receptor activation and signal transduction. This might be a conserved mechanism utilized by the whole GM-CSF/IL-3/IL-5 receptor family.
Protein Data Bank (PDB)
Hansen, G. Hercus, T.R. McClure, B.J. Stomski, F.C. Dottore, M. Powell, J. Ramshaw, H. Woodcock, J.M. Xu, Y. Guthridge, M. McKinstry, W.J. Lopez, A.F. Parker, M.W.; "The structure of the GM-CSF receptor complex reveals a distinct mode of cytokine receptor activation"; Cell(Cambridge,Mass.); (2008) 134:496-507 PubMed:18692472.
author: Jun-ichi Ito