4nkq
From Proteopedia
Structure of a Cytokine Receptor Complex
Structural highlights
Disease[IL3RB_HUMAN] Defects in CSF2RB are the cause of pulmonary surfactant metabolism dysfunction type 5 (SMDP5) [MIM:614370]. SMDP5 is a rare lung disorder due to impaired surfactant homeostasis. It is characterized by alveolar filling with floccular material that stains positive using the periodic acid-Schiff method and is derived from surfactant phospholipids and protein components. Excessive lipoproteins accumulation in the alveoli results in severe respiratory distress.[1] [CSF2R_HUMAN] Defects in CSF2RA are the cause of pulmonary surfactant metabolism dysfunction type 4 (SMDP4) [MIM:300770]. A rare lung disorder due to impaired surfactant homeostasis. It is characterized by alveolar filling with floccular material that stains positive using the periodic acid-Schiff method and is derived from surfactant phospholipids and protein components. Excessive lipoproteins accumulation in the alveoli results in severe respiratory distress.[2] [3] Function[IL3RB_HUMAN] High affinity receptor for interleukin-3, interleukin-5 and granulocyte-macrophage colony-stimulating factor. [CSF2R_HUMAN] Low affinity receptor for granulocyte-macrophage colony-stimulating factor. Transduces a signal that results in the proliferation, differentiation, and functional activation of hematopoietic cells. [CSF2_HUMAN] Cytokine that stimulates the growth and differentiation of hematopoietic precursor cells from various lineages, including granulocytes, macrophages, eosinophils and erythrocytes. Publication Abstract from PubMedGranulocyte-macrophage colony-stimulating factor (GM-CSF) is a pleiotropic cytokine that controls the production and function of blood cells, is deregulated in clinical conditions such as rheumatoid arthritis and leukemia, yet offers therapeutic value for other diseases. Its receptors are heterodimers consisting of a ligand-specific alpha subunit and a betac subunit that is shared with the interleukin (IL)-3 and IL-5 receptors. How signaling is initiated remains an enigma. We report here the crystal structure of the human GM-CSF/GM-CSF receptor ternary complex and its assembly into an unexpected dodecamer or higher-order complex. Importantly, mutagenesis of the GM-CSF receptor at the dodecamer interface and functional studies reveal that dodecamer formation is required for receptor activation and signaling. This unusual form of receptor assembly likely applies also to IL-3 and IL-5 receptors, providing a structural basis for understanding their mechanism of activation and for the development of therapeutics. The structure of the GM-CSF receptor complex reveals a distinct mode of cytokine receptor activation.,Hansen G, Hercus TR, McClure BJ, Stomski FC, Dottore M, Powell J, Ramshaw H, Woodcock JM, Xu Y, Guthridge M, McKinstry WJ, Lopez AF, Parker MW Cell. 2008 Aug 8;134(3):496-507. PMID:18692472[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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