Solution assembly of cytokine receptor ectodomain complexes
- Dartmouth Medical School, Hanover, NH (United States). Dept. of Pharmacology and Toxicology
- Chiron Corp., Emeryville, CA (United States); and others
For the majority of single transmembrane-spanning cell surface receptors, signal transmission across the lipid bilayer barrier involves several discrete components of molecular recognition. The interaction between ligand and the extracellular segment of its cognate receptor (ectodomain) initiates either homomeric or heteromeric association of receptor subunits. Specific recognition among these subunits may then occur between ectodomain regions, within the membrane by interhelical contact or inside the cell between cytoplasmic domains. Any or all of these interactions may contribute to the stability of the signaling complex. It is the characteristics of ligand binding by the ectodomains of these receptors that controls the heteromeric or homomeric nature and the stoichiometry of the complex. Cytokines and their receptors belong to a growing family of macromolecular systems that exhibit these functional features and share many structural similarities as well. Interleukin-2 is a multifunctional cytokine that represents, perhaps, the most complex example to date of ligand recognition among the hematopoietin receptor family. It is the cooperative binding of IL-2 by all three proteins on the surface of activated T-lymphocytes, however, that ultimately results in crosslinking of the {beta}- and {gamma}-subunits and signaling via association of their cytoplasmic domains. Although the high-affinity IL-2R functions as a heterotrimer, heterodimers of the receptor subunits are also physiologically important. The {alpha}/{beta} heterodimer or {open_quotes}pseudo-high affinity{close_quotes} receptor captures IL-2 as a preformed cell surface complex while the {beta}/{gamma} intermediate affinity site exists, in the absence of the {alpha} subunit, on the majority of natural killer cells. We have begun to study stable complexes of cytokine receptor ectodomains of defined composition and that mimic the ligand binding characteristics of the equivalent cell surface receptor sites.
- Research Organization:
- Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
- Sponsoring Organization:
- National Insts. of Health, Bethesda, MD (United States); American Cancer Society, New York, NY (United States); National Science Foundation, Washington, DC (United States); Veterans Administration, Washington, DC (United States); Hitchcock Foundation (United States); Norris Cotton Cancer Center, Hanover, NH (United States)
- DOE Contract Number:
- W-7405-ENG-36
- OSTI ID:
- 110703
- Report Number(s):
- LA-UR-95-2785; CONF-9507177-1; ON: DE96000020; TRN: 95:007250
- Resource Relation:
- Conference: 9. Protein Society symposium, Boston, MA (United States), 8-12 Jul 1995; Other Information: PBD: 1995
- Country of Publication:
- United States
- Language:
- English
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