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000904312 1001_ $$0P:(DE-HGF)0$$aGeorgy, Jacqueline$$b0
000904312 245__ $$aTryptophan (W) at position 37 of murine IL-12/IL-23 p40 is mandatory for binding to IL-12Rβ1 and subsequent signal transduction
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000904312 520__ $$aInterleukin (IL)-12 and IL-23 are composite cytokines consisting of p35/p40 and p19/p40, respectively, which signal via the common IL-12 receptor β1 (IL-12Rβ1) and the cytokine-specific receptors IL-12Rβ2 and IL-23R. Previous data showed that the p40 component interacts with IL-12Rβ1, whereas p19 and p35 subunits solely bind to IL-23R and IL-12Rβ2, resulting in tetrameric signaling complexes. In the absence of p19 and p35, p40 forms homodimers and may induce signaling via IL-12Rβ1 homodimers. The critical amino acids of p19 and p35 required for binding to IL-23R and IL-12Rβ2 are known, and two regions of p40 critical for binding to IL-12Rβ1 have recently been identified. In order to characterize the involvement of the N-terminal region of p40 in binding to IL-12Rβ1, we generated deletion variants of the p40-p19 fusion cytokine. We found that an N-terminal deletion variant missing amino acids M23 to P39 failed to induce IL-23-dependent signaling and did not bind to IL-12Rβ1, whereas binding to IL-23R was maintained. Amino acid replacements showed that p40W37K largely abolished IL-23-induced signal transduction and binding to IL-12Rβ1, but not binding to IL-23R. Combining p40W37K with D36K and T38K mutations eliminated the biological activity of IL-23. Finally, homodimeric p40D36K/W37K/T38K did not interact with IL-12Rβ1, indicating binding of homodimeric p40 to IL-12Rβ1 is comparable to the interaction of IL-23/IL-12 and IL-12Rβ1. In summary, we have defined D36, W37, and T38 as hotspot amino acids for the interaction of IL-12/IL-23 p40 with IL-12Rβ1. Structural insights into cytokine–cytokine receptor binding are important to develop novel therapeutic strategies.
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000904312 7001_ $$0P:(DE-HGF)0$$aArlt, Yvonne$$b1
000904312 7001_ $$0P:(DE-HGF)0$$aMoll, Jens M.$$b2
000904312 7001_ $$0P:(DE-HGF)0$$aOuzin, Meryem$$b3
000904312 7001_ $$00000-0002-7185-0016$$aWeitz, Hendrik T.$$b4
000904312 7001_ $$0P:(DE-Juel1)145165$$aGremer, Lothar$$b5
000904312 7001_ $$0P:(DE-Juel1)132029$$aWillbold, Dieter$$b6
000904312 7001_ $$0P:(DE-HGF)0$$aGrötzinger, Joachim$$b7
000904312 7001_ $$0P:(DE-HGF)0$$aThives-Kurenbach, Felix$$b8
000904312 7001_ $$00000-0001-9932-1055$$aScheller, Jürgen$$b9
000904312 7001_ $$00000-0002-6675-5313$$aFloss, Doreen M.$$b10$$eCorresponding author
000904312 773__ $$0PERI:(DE-600)1474604-9$$a10.1016/j.jbc.2021.101295$$gVol. 297, no. 5, p. 101295 -$$n5$$p101295 -$$tThe journal of biological chemistry$$v297$$x0021-9258$$y2021
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