TY - JOUR
T1 - A ligand peptide motif selected from a cancer patient is a receptor-interacting site within human interleukin-11
AU - Cardó-Vila, Marina
AU - Zurita, Amado J.
AU - Giordano, Ricardo J.
AU - Sun, Jessica
AU - Rangel, Roberto
AU - Guzman-Rojas, Liliana
AU - Anobom, Cristiane D.
AU - Valente, Ana P.
AU - Almeida, Fábio C.L.
AU - Lahdenranta, Johanna
AU - Kolonin, Mikhail G.
AU - Arap, Wadih
AU - Pasqualini, Renata
PY - 2008
Y1 - 2008
N2 - Interleukin-11 (IL-11) is a pleiotropic cytokine approved by the FDA against chemotherapy-induced thrombocytopenia. From a combinatorial selection in a cancer patient, we isolated an IL-11-like peptide mapping to domain I of the IL-11 (sequence CGRRAGGSC). Although this motif has ligand attributes, it is not within the previously characterized interacting sites. Here we design and validate in-tandem binding assays, site-directed mutagenesis and NMR spectroscopy to show (i) the peptide mimics a receptor-binding site within IL-11, (ii) the binding of CGRRAGGSC to the IL-11Rα is functionally relevant, (iii) Arg4 and Ser8 are the key residues mediating the interaction, and (iv) the IL-11-like motif induces cell proliferation through STAT3 activation. These structural and functional results uncover an as yet unrecognized receptor-binding site in human IL-11. Given that IL-11Rα has been proposed as a target in human cancer, our results provide clues for the rational design of targeted drugs.
AB - Interleukin-11 (IL-11) is a pleiotropic cytokine approved by the FDA against chemotherapy-induced thrombocytopenia. From a combinatorial selection in a cancer patient, we isolated an IL-11-like peptide mapping to domain I of the IL-11 (sequence CGRRAGGSC). Although this motif has ligand attributes, it is not within the previously characterized interacting sites. Here we design and validate in-tandem binding assays, site-directed mutagenesis and NMR spectroscopy to show (i) the peptide mimics a receptor-binding site within IL-11, (ii) the binding of CGRRAGGSC to the IL-11Rα is functionally relevant, (iii) Arg4 and Ser8 are the key residues mediating the interaction, and (iv) the IL-11-like motif induces cell proliferation through STAT3 activation. These structural and functional results uncover an as yet unrecognized receptor-binding site in human IL-11. Given that IL-11Rα has been proposed as a target in human cancer, our results provide clues for the rational design of targeted drugs.
UR - https://www.scopus.com/pages/publications/55149092968
UR - https://www.scopus.com/pages/publications/55149092968#tab=citedBy
U2 - 10.1371/journal.pone.0003452
DO - 10.1371/journal.pone.0003452
M3 - Article
C2 - 18941632
AN - SCOPUS:55149092968
SN - 1932-6203
VL - 3
JO - PloS one
JF - PloS one
IS - 10
M1 - e3452
ER -