Structural organization of a full-length gp130/LIF-R cytokine receptor transmembrane complex.
gp130 is a shared receptor for at least nine cytokines and can signal either as a homodimer or as a heterodimer with Leukemia Inhibitory Factor Receptor (LIF-R). Here, we biophysically and structurally characterize the full-length, transmembrane form of a quaternary cytokine receptor complex consisting of gp130, LIF-R, the cytokine Ciliary Neurotrophic Factor (CNTF), and its alpha receptor (CNTF-Ralpha). Thermodynamic analysis indicates that, unlike the cooperative assembly of the symmetric gp130/Interleukin-6/IL-6Ralpha hexameric complex, CNTF/CNTF-Ralpha heterodimerizes gp130 and LIF-R via noncooperative energetics to form an asymmetric 1:1:1:1 complex. Single particle electron microscopic analysis of the full-length gp130/LIF-R/CNTF-Ralpha/CNTF quaternary complex elucidates an asymmetric structural arrangement, in which the receptor extracellular and transmembrane segments join as a continuous, rigid unit, poised to sensitively transduce ligand engagement to the membrane-proximal intracellular signaling regions. These studies also enumerate the organizing principles for assembly of the "tall" class of gp130 family cytokine receptor complexes including LIF, IL-27, IL-12, and others.
Skiniotis
Georgios
G
Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA.
Lupardus
Patrick J
PJ
Martick
Monika
M
Walz
Thomas
T
Garcia
K Christopher
KC
D000818:Animals; D020934:Ciliary Neurotrophic Factor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D018360:Crystallography, X-Ray; D050822:Cytokine Receptor gp130 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000737:chemistry* / Q000648:ultrastructure; D020836:Protein Structure, Quaternary; D020801:Receptor, Ciliary Neurotrophic Factor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D053606:Receptors, OSM-LIF / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013816:Thermodynamics
D020934:Ciliary Neurotrophic Factor; D046912:Multiprotein Complexes; D020801:Receptor, Ciliary Neurotrophic Factor; D053606:Receptors, OSM-LIF; D050822:Cytokine Receptor gp130
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