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-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.
Hymowitz
S G
SG
Department of Protein Engineering, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Filvaroff
E H
EH
Yin
J P
JP
Lee
J
J
Cai
L
L
Risser
P
P
Maruoka
M
M
Mao
W
W
Foster
J
J
Kelley
R F
RF
Pan
G
G
Gurney
A L
AL
de Vos
A M
AM
Starovasnik
M A
MA
D000595:Amino Acid Sequence; D002356:Cartilage / Q000378:metabolism; D018360:Crystallography, X-Ray; D003553:Cystine / Q000737:chemistry; D019281:Dimerization; D006801:Humans; D020381:Interleukin-17 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D005810:Multigene Family; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000302:isolation & purification; D018123:Receptors, Interleukin / Q000378:metabolism*; D053722:Receptors, Interleukin-17; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D013601:T-Lymphocytes / Q000378:metabolism; D014018:Tissue Distribution
C109985:IL17RA protein, human; D020381:Interleukin-17; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D053722:Receptors, Interleukin-17; D011994:Recombinant Proteins; D003553:Cystine