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PDB:3cxe

Protein Name

GM-CSF/GM-CSF receptor complex

Species

Homo sapiens

Biological Context

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.

(Figure.1) Cytokines Serve as Intercellular Transduction Signals

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.

Structure Description

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).

(Figure.2) The Structure of the GM-CSF/GM-CSF Receptor Complex

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).

(Figure.3 The three main interfaces in the GM-CSF/GM-CSF receptor complex) Site 1: Interface between GM-CSF and Bc The key interaction that contributes to the binding of GM-CSF to Bc is a hydrogen bond formed between E21 of GM-CSF and Y421 of Bc. The two other cytokine, IL-3 and IL-5, also conserve the E22 and E13 respectively in the corresponding regions of E21 of GM-CSF. Therefore, it is suggested that these glutamic acids(E) have a important role in binging to the cytokine receptor. Site 2: Interface between GM-CSF and GMRa The two helices(11-23, 112-118) of GM-CSF have interactions with the two loops(241-251, 299-305) of GMRa respectively. The interactions are considered to contribute to the binding of GM-CSF and GMRa. Site 3: Interface between GMRa and Bc GMRa forms an extensive interaction with Bc. It provides additional interacting surfaces between GMRa and Bc, which enhances the overall binding affinity of GM-CSF for the GM-CSF receptor. The mutagenesis studies, not only structural observation, verified that the inter-residue interactions mentioned above are important for the binding of GM-CSF and GM-CSF receptor.

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.

(Structural basis)
The GM-CSF receptor does not have intrinsic tyrosine kinase activity but associates with the tyrosine kinase(JAK2) in the cytoplasmic domains of Bc, which is required for Bc transphosphorylation. JAK2 bound with Bc is able to dimerize and transphosphorylate in the dodecamer complex but not in the hexamer complex. At the cue of transphosphorylation the intracellular signaling is initialized. (Refer to Figure.4).

(Figure.4) Model of Signal Transduction

(Experimental basis)
A higher-order dodecamer complex composed of two hexamers that interact through another interface called site 4. The mutations at the Site 4 greatly reduced signaling activity, not only from GM-CSF but also from IL-3.

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)

• PDB Summary: 3cxe
• View Structure (jV3)

References

Source

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.

Others

• UniProt:P32927 UniProt:P04141 UniProt:P15509

author: Jun-ichi Ito

Japanese version:PDB:3cxe