Structural reorganization of the interleukin-7 signaling complex.

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TitleStructural reorganization of the interleukin-7 signaling complex.
Publication TypeJournal Article
Year of Publication2012
AuthorsMcElroy, CA, Holland, PJ, Zhao, P, Lim, J-M, Wells, L, Eisenstein, E, Walsh, STR
JournalProc Natl Acad Sci U S A
Date Published2012 Feb 14
KeywordsDimerization, Interleukin-7, Ligands, Protein Binding, Protein Conformation, Signal Transduction, X-Ray Diffraction

We report here an unliganded receptor structure in the common gamma-chain (γ(c)) family of receptors and cytokines. The crystal structure of the unliganded form of the interleukin-7 alpha receptor (IL-7Rα) extracellular domain (ECD) at 2.15 Å resolution reveals a homodimer forming an "X" geometry looking down onto the cell surface with the C termini of the two chains separated by 110 Å and the dimer interface comprising residues critical for IL-7 binding. Further biophysical studies indicate a weak association of the IL-7Rα ECDs but a stronger association between the γ(c)/IL-7Rα ECDs, similar to previous studies of the full-length receptors on CD4(+) T cells. Based on these and previous results, we propose a molecular mechanism detailing the progression from the inactive IL-7Rα homodimer and IL-7Rα-γ(c) heterodimer to the active IL-7-IL-7Rα-γ(c) ternary complex whereby the two receptors undergo at least a 90° rotation away from the cell surface, moving the C termini of IL-7Rα and γ(c) from a distance of 110 Å to less than 30 Å at the cell surface. This molecular mechanism can be used to explain recently discovered IL-7- and γ(c)-independent gain-of-function mutations in IL-7Rα from B- and T-cell acute lymphoblastic leukemia patients. The mechanism may also be applicable to other γ(c) receptors that form inactive homodimers and heterodimers independent of their cytokines.

Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID22308406
PubMed Central IDPMC3289338
Grant ListAI72142 / AI / NIAID NIH HHS / United States
P41RR018502 / RR / NCRR NIH HHS / United States