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
Volume109
Issue7
Pagination2503-8
Date Published2012 Feb 14
ISSN1091-6490
KeywordsDimerization, Interleukin-7, Ligands, Protein Binding, Protein Conformation, Signal Transduction, X-Ray Diffraction
Abstract

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.

DOI10.1073/pnas.1116582109
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