Elucidation of the Interleukin-15 Binding Site on Its Alpha Receptor by NMR

The cytokine interleukin-15 (IL-15) signals through the formation of a quaternary receptor complex composed of an IL-15-specific α receptor, together with β and γc receptors that are shared with interleukin-2 (IL-2). The initiating step in the formation of this signaling complex is the interaction b...

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Bibliographic Details
Published in:Biochemistry (Easton) 2007-08, Vol.46 (33), p.9453-9461
Main Authors: Hanick, Nicole A, Rickert, Mathias, Varani, Luca, Bankovich, Alexander J, Cochran, Jennifer R, Kim, David M, Surh, Charles D, Garcia, K. Christopher
Format: Article
Language:English
Subjects:
Binding Sites
CD8-Positive T-Lymphocytes - immunology
Humans
Interleukin-15 - chemistry
Interleukin-15 - genetics
Interleukin-15 - metabolism
Interleukin-15 Receptor alpha Subunit - chemistry
Interleukin-15 Receptor alpha Subunit - genetics
Interleukin-15 Receptor alpha Subunit - metabolism
Magnetic Resonance Spectroscopy
Models, Molecular
Protein Conformation
Protein Interaction Mapping
Recombinant Proteins - chemistry
Recombinant Proteins - genetics
Recombinant Proteins - metabolism
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Summary:The cytokine interleukin-15 (IL-15) signals through the formation of a quaternary receptor complex composed of an IL-15-specific α receptor, together with β and γc receptors that are shared with interleukin-2 (IL-2). The initiating step in the formation of this signaling complex is the interaction between IL-15 and IL-15Rα, which is a single sushi domain bearing strong structural homology to one of the two sushi domains of IL-2Rα. The crystal structure of the IL2-Rα/IL-2 complex has been determined, however little is known about the analogous IL-15Rα/IL-15 binding interaction. Here we show that recombinant IL-15 can be overexpressed as a stable complex in the presence of its high affinity receptor, IL-15Rα. We find that this complex is 10-fold more active than IL-15 alone in stimulating proliferation and survival of memory phenotype CD8 T cells. To probe the ligand/receptor interface, we used solution NMR to map chemical shifts on 15N-labeled IL-15Rα in complex with unlabeled IL-15. Our results predict that the binding surface on IL-15Rα involves strands C and D, similar to IL-2Rα. The interface, as predicted here, leaves open the possibility of trans-presentation of IL-15 by IL-15Rα on an opposing cell.
ISSN:0006-2960
1520-4995
DOI:10.1021/bi700652f