IL-17s adopt a cystine knot fold: structure and activity of a novel cytokine, IL-17F, and implications for receptor binding

The proinflammatory cytokine interleukin 17 (IL‐17) is the founding member of a family of secreted proteins that elicit potent cellular responses. We report a novel human IL‐17 homolog, IL‐17F, and show that it is expressed by activated T cells, can stimulate production of other cytokines such as IL...

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Bibliographic Details
Published in:The EMBO journal 2001-10, Vol.20 (19), p.5332-5341
Main Authors: Hymowitz, Sarah G., Filvaroff, Ellen H., Yin, JianPing, Lee, James, Cai, Liping, Risser, Philip, Maruoka, Miko, Mao, Weiguang, Foster, Jessica, Kelley, Robert F., Pan, Guohua, Gurney, Austin L., de Vos, Abraham M., Starovasnik, Melissa A.
Format: Article
Language:English
Subjects:
activated T cell
Amino Acid Sequence
Cartilage - metabolism
Crystallography, X-Ray
Cystine - chemistry
cystine knot
cytokines
Dimerization
Growth factors
Humans
IL-17
interleukin 17 receptors
Interleukin-17 - chemistry
Interleukin-17 - genetics
Interleukin-17 - metabolism
Models, Molecular
Molecular Sequence Data
Multigene Family
Protein Structure, Tertiary
Receptors, Interleukin - metabolism
Receptors, Interleukin-17
Recombinant Proteins - chemistry
Recombinant Proteins - metabolism
RNA, Messenger - isolation & purification
Sequence Homology, Amino Acid
T-Lymphocytes - metabolism
Tissue Distribution
TrkA protein
X-ray crystallography
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Summary:The proinflammatory cytokine interleukin 17 (IL‐17) is the founding member of a family of secreted proteins that elicit potent cellular responses. We report a novel human IL‐17 homolog, IL‐17F, and show that it is expressed by activated T cells, can stimulate production of other cytokines such as IL‐6, IL‐8 and granulocyte colony‐stimulating factor, and can regulate cartilage matrix turnover. Unexpectedly, the crystal structure of IL‐17F reveals that IL‐17 family members adopt a monomer fold typical of cystine knot growth factors, despite lacking the disulfide responsible for defining the canonical ‘knot’ structure. IL‐17F dimerizes in a parallel manner like neurotrophins, and features an unusually large cavity on its surface. Remarkably, this cavity is located in precisely the same position where nerve growth factor binds its high affinity receptor, TrkA, suggesting further parallels between IL‐17s and neurotrophins with respect to receptor recognition.
ISSN:0261-4189
1460-2075
1460-2075
DOI:10.1093/emboj/20.19.5332