Tryptophan (W) at position 37 of murine IL-12/IL-23 p40 is mandatory for binding to IL-12Rβ1 and subsequent signal transduction

Abstract

Interleukin (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. Interleukin (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. The interleukin (IL-)12 type cytokines IL-12 and IL-23 play critical roles in a variety of innate and acquired immune responses. Misregulation eventually causes chronic autoimmune responses, and Ustekinumab, an antibody blocking IL-12/IL-23 signaling, was recently approved for psoriasis, psoriatic arthritis, Crohn’s disease, and ulcerative colitis (1Floss D.M. Moll J.M. Scheller J. IL-12 and IL-23-close relatives with structural homologies but distinct immunological functions.Cells. 2020; 9: 2184Crossref Scopus (14) Google Scholar). Knowledge about structure and composition of the IL-12/IL-23 cytokine:receptor complexes, as well as signaling components, offered new possibilities for effective targeting strategies of both cytokines. In general, cytokines of the IL-6/IL-12 family activate the JAK/STAT pathway, the MAPK pathway, and the PI3K/AKT pathway. Albeit, STAT1, 3, 4, and 5 are activated by IL-12 and IL-23, STAT4 remains the dominant signaling molecule for IL-12 and STAT3 for IL-23 (2Tait Wojno E.D. Hunter C.A. Stumhofer J.S. The immunobiology of the interleukin-12 family: Room for discovery.Immunity. 2019; 50: 851-870Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar). IL-12 cytokines function as heterodimers comprised of α and β subunits. IL-12 and IL-23 share their β subunit p40, which is linked to α subunits through disulfide bonds formed between C199 of p40 and C96 of p35 or C73 of p19 for human IL-12 and IL-23, respectively (3Wolf S.F. Temple P.A. Kobayashi M. Young D. Dicig M. Lowe L. Dzialo R. Fitz L. Ferenz C. Hewick R.M. Cloning of cDNA for natural killer cell stimulatory factor, a heterodimeric cytokine with multiple biologic effects on T and natural killer cells.J. Immunol. 1991; 146: 3074-3081PubMed Google Scholar, 4Gubler U. Chua A.O. Schoenhaut D.S. Dwyer C.M. McComas W. Motyka R. Nabavi N. Wolitzky A.G. Quinn P.M. Familletti P.C. Gately M.K. Coexpression of two distinct genes is required to generate secreted bioactive cytotoxic lymphocyte maturation factor.Proc. Natl. Acad. Sci. U. S. A. 1991; 88: 4143-4147Crossref PubMed Scopus (560) Google Scholar, 5Parham C. Chirica M. Timans J. Vaisberg E. Travis M. Cheung J. Pflanz S. Zhang R. Singh K.P. Vega F. To W. Wagner J. O'Farrell A.M. McClanahan T. Zurawski S. et al.A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rbeta1 and a novel cytokine receptor subunit, IL-23R.J. Immunol. 2002; 168: 5699-5708Crossref PubMed Scopus (1031) Google Scholar). Interactions of IL-12 type cytokines with their cognate receptors follow the “site 1-2-3” structural model based on the structure of IL-6, IL-6R and gp130 (6Jones L.L. Vignali D.A. Molecular interactions within the IL-6/IL-12 cytokine/receptor superfamily.Immunol. Res. 2011; 51: 5-14Crossref PubMed Scopus (80) Google Scholar, 7Vignali D.A. Kuchroo V.K. IL-12 family cytokines: Immunological playmakers.Nat. Immunol. 2012; 13: 722-728Crossref PubMed Scopus (738) Google Scholar, 8Collison L.W. Delgoffe G.M. Guy C.S. Vignali K.M. Chaturvedi V. Fairweather D. Satoskar A.R. Garcia K.C. Hunter C.A. Drake C.G. Murray P.J. Vignali D.A. The composition and signaling of the IL-35 receptor are unconventional.Nat. Immunol. 2012; 13: 290-299Crossref PubMed Scopus (298) Google Scholar). p40 uses the same binding site 1 of domains 2 and 3 to interact with both p19 and p35 (9Lupardus P.J. Garcia K.C. The structure of interleukin-23 reveals the molecular basis of p40 subunit sharing with interleukin-12.J. Mol. Biol. 2008; 382: 931-941Crossref PubMed Scopus (81) Google Scholar). Aside from the central cysteine residues, R207 and Y211 in murine p35, R211 and Y215 in human p35 are critical for association with p40 (10Jones L.L. Chaturvedi V. Uyttenhove C. Van Snick J. Vignali D.A. Distinct subunit pairing criteria within the heterodimeric IL-12 cytokine family.Mol. Immunol. 2012; 51: 234-244Crossref PubMed Scopus (37) Google Scholar). For murine IL-23, mutations in I176, A178, and R179 of p19 prevent the formation of IL-23 (11Schröder J. Moll J.M. Baran P. Grötzinger J. Scheller J. Floss D.M. Non-canonical interleukin 23 receptor complex assembly: p40 protein recruits interleukin 12 receptor beta1 via site II and induces p19/interleukin 23 receptor interaction via site III.J. Biol. Chem. 2015; 290: 359-370Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar). The receptor complex interfaces between the cytokine subunits of IL-12/IL-23, and the respective receptors IL-12Rβ1 and IL-12Rβ2 or IL-23R are named site 2 and site 3, respectively. Based on the structure of IL-23, our work showed that murine p19W157 is the hotspot amino acid for site 3 interaction with murine IL-23R (9Lupardus P.J. Garcia K.C. The structure of interleukin-23 reveals the molecular basis of p40 subunit sharing with interleukin-12.J. Mol. Biol. 2008; 382: 931-941Crossref PubMed Scopus (81) Google Scholar, J. Moll J.M. Baran P. Grötzinger J. Scheller J. Floss D.M. Non-canonical interleukin 23 receptor complex assembly: p40 protein recruits interleukin 12 receptor beta1 via site II and induces p19/interleukin 23 receptor interaction via site III.J. Biol. Chem. 2015; 290: 359-370Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar). For p40, the domains and are required to the binding site 3 of IL-23 to IL-23R (11Schröder J. Moll J.M. Baran P. Grötzinger J. Scheller J. Floss D.M. Non-canonical interleukin 23 receptor complex assembly: p40 protein recruits interleukin 12 receptor beta1 via site II and induces p19/interleukin 23 receptor interaction via site III.J. Biol. Chem. 2015; 290: 359-370Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar). In the structure of human in complex with a antibody targeting human IL-23 was L. R. Van L. S. S. D. F. M. S. Structural of human cytokine IL-23 by cognate IL-23 receptor of the receptor Full Text Full Text PDF PubMed Scopus Google Scholar). to that of and in an human p19 cytokine variant on human IL-23 For site 3 interaction between IL-12 and IL-12Rβ2, we that the site 3 in human p35 binding to IL-12Rβ2 in a A. A. S. Moll J.M. Grötzinger J. J. Scheller J. Floss D.M. site 3 interactions of interleukin 12 and interleukin 23 with their cognate murine and human Biol. Chem. 2020; Full Text Full Text PDF PubMed Scopus Google Scholar). site 2 is by the cytokine α interaction of with IL-12Rβ1 is data that are for interaction and that p40 interacts with IL-12Rβ1. of secreted p40 to IL-12Rβ1 and is an effective of IL-12 and IL-23 F. S. S. S. E. E. T. The interleukin-12 subunit p40 effects of the interleukin-12 J. Immunol. PubMed Scopus Google Scholar, S. D. P. Familletti P.C. U. Gately M.K. interleukin-12 p40 IL-12 J. Immunol. PubMed Scopus Google Scholar, S. M. A. M. The secreted of the p40 subunit of interleukin (IL)-12 IL-23 and PubMed Scopus Google Scholar). p40 IL-12Rβ1, but not IL-12Rβ2, to autoimmune S. M. M. A. J. R. IL-12 p40 is from IL-12 family to IL-12Rbeta1 and Natl. Acad. Sci. U. S. A. 2020; PubMed Scopus Google Scholar). IL-12 or IL-23 signaling is by to an on 1 of human p40 consisting of and interaction with IL-12Rβ1 J. A. A. J. Structural basis for the of IL-12 and IL-23 by Mol. Biol. PubMed Scopus Google Scholar). data IL-12 and IL-23 bind to IL-12Rβ1 via the binding of the p40 with the of A. S. C. M. C. Van M. C. of human Interleukin 23 by by the structure of Immunol. PubMed Scopus Google Scholar). In we showed that deletion of in murine p40 interaction of with murine IL-12Rβ1 p40 the site 2 interaction of p19 (11Schröder J. Moll J.M. Baran P. Grötzinger J. Scheller J. Floss D.M. Non-canonical interleukin 23 receptor complex assembly: p40 protein recruits interleukin 12 receptor beta1 via site II and induces p19/interleukin 23 receptor interaction via site III.J. Biol. Chem. 2015; 290: 359-370Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar). of human IL-12Rβ1 and the IL-23 receptor complex have been by and K.M. L. P.J. C. Garcia K.C. Structural basis for IL-12 and IL-23 receptor sharing reveals a for on T Full Text Full Text PDF PubMed Scopus Google Scholar). In of IL-12 and IL-23 have been K.M. L. P.J. C. Garcia K.C. Structural basis for IL-12 and IL-23 receptor sharing reveals a for on T Full Text Full Text PDF PubMed Scopus Google Scholar). Based on et a binding formed by a in p40 and and a on p40 and IL-12 and IL-23 variants with multiple mutations in two of p40 the of the cytokines. the of not been K.M. L. P.J. C. Garcia K.C. Structural basis for IL-12 and IL-23 receptor sharing reveals a for on T Full Text Full Text PDF PubMed Scopus Google Scholar). we that the N-terminal region of p40 the binding to IL-12Rβ1. we of p40 as a amino acid for site 2 that the N-terminal region of gp130 is required for formation of the receptor complex The of gp130 is critical for the formation of the receptor PubMed Scopus Google and the activity of IL-12 and IL-23 via binding to of p40 J. A. A. J. Structural basis for the of IL-12 and IL-23 by Mol. Biol. PubMed Scopus Google we that the N-terminal region of p40 is in binding to IL-12Rβ1. In order to our we generated N-terminal deletion variants of murine p40 in murine is a fusion protein of and murine p19 by a R. Timans Vega F. N. J. Singh F. Vaisberg E. T. M. D. et p19 protein to a IL-23, with biological as well as distinct from 13: Full Text Full Text PDF PubMed Scopus Google Scholar, D.M. S. T. J. Grötzinger J. S. Scheller J. of and STAT3 in the of the interleukin 23 Biol. Chem. Full Text Full Text PDF PubMed Scopus (37) Google Scholar). largely the formation of p40 which may have in our as S. D. P. Familletti P.C. U. Gately M.K. interleukin-12 p40 IL-12 J. Immunol. PubMed Scopus Google Scholar). of the deletion variants and an signal and an N-terminal of the amino acids of secreted p40 between and the of p40 is about The structure of IL-23 reveals that the of p40 is for interaction with IL-12Rβ1 p40 by a of or of to with to L. R. Van L. S. S. D. F. M. S. Structural of human cytokine IL-23 by cognate IL-23 receptor of the receptor Full Text Full Text PDF PubMed Scopus Google Scholar). of murine with murine and murine IL-12Rβ1 on or D.M. S. T. J. Grötzinger J. S. Scheller J. of and STAT3 in the of the interleukin 23 Biol. Chem. Full Text Full Text PDF PubMed Scopus (37) Google Scholar). of or deletion variants to was by but not by the deletion variants In of cell from have been for cell to activity of cytokines with of that of cell is with of of STAT3 and which are of the signal showed that was to signaling that the amino acids from to T38 are critical for signal To binding of to is in the receptor with two deletion variants a both cytokine variants bind For with murine IL-12Rβ1 and or variants of in of and and both and with interaction with was for and our data that the N-terminal region of p40 from to T38 binding to hotspot amino acids within the amino acid to T38 of p40 may to IL-12Rβ1 the p40 mutations in T38K the was as hotspot amino acid for interaction of p40 with IL-12Rβ1 K.M. L. P.J. C. Garcia K.C. Structural basis for IL-12 and IL-23 receptor sharing reveals a for on T Full Text Full Text PDF PubMed Scopus Google Scholar). is the of a formed by and of the IL-12Rβ1 as well as of p40 K.M. L. P.J. C. Garcia K.C. Structural basis for IL-12 and IL-23 receptor sharing reveals a for on T Full Text Full Text PDF PubMed Scopus Google Scholar). In general, we the amino acid to or amino acids for we the amino acid into a acid was to by of a amino we generated and with cell of the variants and was The of STAT3 and signaling for of p40 T38 or on IL-23 into or was comparable to the of amino acids into of and by and structure by the that effects are to a of the with of and and a structure by a of or and an of or respectively, which is in with structure and and The structure of is to the structure of and that the not the structure of the by binding of to the IL-23R with comparable to and of the interaction between the cytokine and the respective of and variants binding to and and on a and of or variants a of on a in a new of and variants binding to and and on a and of or variants a of on a for binding found for the variant to IL-12Rβ1 may T38K formation with may in the interaction of p40 to IL-12Rβ1 through of interaction with IL-12Rβ1 D36K in of T38K and D36K the of T38K interaction with binding to IL-23R and of in and in binding to IL-12Rβ1 and To the of in binding of IL-23 to the IL-12Rβ1, we mutations D36, W37, or T38 and the resulting variants in 3, and of STAT3 and was in and with and of by was by the with to a of the interactions formed with and of IL-12Rβ1 and the biological activity of the that of p40 is for binding of IL-23 to IL-12Rβ1. we fusion for our to the of for binding of natural IL-23 to IL-12Rβ1, we p19 and p40 or respectively, into and of 4, and showed interaction with both whereas to IL-23R but not to IL-12Rβ1 we that the is for p40 binding to IL-12 and IL-23 both interact with the IL-12Rβ1 via the p40 subunit, whereas p35 interacts with IL-12Rβ2 and p19 with the IL-23R. In order to is required for binding of IL-12 to IL-12Rβ1, we into and the in to mutations into we to and receptor binding via and and by a of or and an of or a structure in with the structure of and and in of and binding to IL-12Rβ2 comparable to 1 and We showed that IL-12 of and STAT3 in D.M. T. J. L. S. Scheller J. the binding of interleukin 12 receptor beta1 and interleukin 23 receptor to Biol. PubMed Scopus (27) Google have STAT4 protein and for of STAT4 J. U. between the regions of the interleukin-12 receptor subunits beta1 and and Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). was on and interaction of with IL-12Rβ2 but not with IL-12Rβ1, whereas both IL-12Rβ1 and IL-12Rβ2 and a we site 3 variant which interacts with IL-12Rβ1 and not IL-12Rβ2 A. A. S. Moll J.M. Grötzinger J. J. Scheller J. Floss D.M. site 3 interactions of interleukin 12 and interleukin 23 with their cognate murine and human Biol. Chem. 2020; Full Text Full Text PDF PubMed Scopus Google Scholar). In summary, our data that is in p40 for interaction with IL-12Rβ1. p19 or p35, p40 forms the linked p40 which interacts with IL-12Rβ1 to IL-12 and IL-23. We and in and showed formation of by by of p40 failed to interact with and to data for human p40 variants and their binding to human IL-12Rβ1 and human IL-23R and The of murine and human p40 is in and and of respective by but not by and of p40 in IL-23, or as homodimeric p40 our data that the binding of p40 to IL-12Rβ1 is for and on the N-terminal amino acids IL-12 and IL-23 are the cytokines of the cytokine family and share structural cytokines are composed of the β subunit p40, which binding to the common IL-12Rβ1. The receptors IL-12Rβ2 and IL-23R bind to the α subunits p35 and respectively (1Floss D.M. Moll J.M. Scheller J. IL-12 and IL-23-close relatives with structural homologies but distinct immunological functions.Cells. 2020; 9: 2184Crossref Scopus (14) Google Scholar). of and p40 is by domains 2 and 3 of p40 indicating that domains are for IL-12Rβ1 structure of the IL-23 receptor complex and of the IL-12 and IL-23 receptor have been K.M. L. P.J. C. Garcia K.C. Structural basis for IL-12 and IL-23 receptor sharing reveals a for on T Full Text Full Text PDF PubMed Scopus Google Scholar). The p40 subunit interacts with IL-12Rβ1 indicating a function of p40 in the of IL-12 and IL-23 signaling K.M. L. P.J. C. Garcia K.C. Structural basis for IL-12 and IL-23 receptor sharing reveals a for on T Full Text Full Text PDF PubMed Scopus Google Scholar). The is a composite which interact with IL-6R binding to In to p40, IL-6R not to binding to the N-terminal region of gp130 is for interaction with The of gp130 is critical for the formation of the receptor PubMed Scopus Google Scholar). we the of the of p40 for binding to IL-12Rβ1. of the N-terminal amino acids on the biological activity of deletion of p40 amino acids to T38 abolished IL-23 biological activity and binding to IL-12Rβ1. with the structural data from and that the is formed by a and a on p40 to the and K.M. L. P.J. C. Garcia K.C. Structural basis for IL-12 and IL-23 receptor sharing reveals a for on T Full Text Full Text PDF PubMed Scopus Google Scholar). by deletion of amino acids to we 1 in 1 of p40, which is important for binding of the IL-12/IL-23 antibody J. A. A. J. Structural basis for the of IL-12 and IL-23 by Mol. Biol. PubMed Scopus Google Scholar). Structural of the p40 of showed interaction with within the of p40 was found to the critical amino acid for the interaction of with p40 J. A. A. J. Structural basis for the of IL-12 and IL-23 by Mol. Biol. PubMed Scopus Google Scholar). Based on we are to and the amino acids and T38 as hotspot amino acids for interaction with IL-12Rβ1 via site IL-12/IL-23 signaling and binding of p40 to IL-12Rβ1 for p40W37K and for amino acids are between and binding of murine and human p40 to IL-12Rβ1 is largely in For Ustekinumab, which to human but not to murine p40, amino acids of p40 1 the binding J. A. A. J. Structural basis for the of IL-12 and IL-23 by Mol. Biol. PubMed Scopus Google Scholar). Amino acids of 2 are largely between and which may not interact with murine showed that in and of the 1 are important within the binding to J. A. A. J. Structural basis for the of IL-12 and IL-23 by Mol. Biol. PubMed Scopus Google Scholar). In not been not that amino acids and are critical for interaction with IL-12Rβ1, may bind to the and may interaction by structural the IL-23/IL-12 interacts with the N-terminal of human p40 and with the binding of A. S. C. M. C. Van M. C. of human Interleukin 23 by by the structure of Immunol. PubMed Scopus Google Scholar). We the within p40 as a hotspot amino acid for interaction of p40 and IL-12Rβ1 K.M. L. P.J. C. Garcia K.C. Structural basis for IL-12 and IL-23 receptor sharing reveals a for on T Full Text Full Text PDF PubMed Scopus Google Scholar). In our we did not amino which for the interaction of IL-12Rβ1 and The of our was to critical hotspot amino acid to interaction between p40 and IL-12Rβ1 the interaction of and the interaction of IL-12 and IL-23 with IL-12Rβ2 and respectively. We are that of amino acid may the within the and not in interaction with IL-12Rβ1. we have by recently structural data that the variant the binding from binding into We that p40 deletion and variants are and in a that binding to as a interaction with the receptor In our that of p40 is for interaction with IL-12Rβ1 both in IL-12 and IL-23 and in the p40 and from the of and with and or and D.M. S. T. J. Grötzinger J. S. Scheller J. of and STAT3 in the of the interleukin 23 Biol. Chem. Full Text Full Text PDF PubMed Scopus (37) Google Scholar, D.M. T. J. L. S. Scheller J. the binding of interleukin 12 receptor beta1 and interleukin 23 receptor to Biol. PubMed Scopus (27) Google Scholar). cell in with and with in a of cell was by of cell from a as by and from and to STAT3 MAPK and MAPK from from and from protein and protein from Cloning of an N-terminal and a for murine murine murine p40 and murine p19 was (11Schröder J. Moll J.M. Baran P. Grötzinger J. Scheller J. Floss D.M. Non-canonical interleukin 23 receptor complex assembly: p40 protein recruits interleukin 12 receptor beta1 via site II and induces p19/interleukin 23 receptor interaction via site III.J. Biol. Chem. 2015; 290: 359-370Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar, D.M. S. T. J. Grötzinger J. S. Scheller J. of and STAT3 in the of the interleukin 23 Biol. Chem. Full Text Full Text PDF PubMed Scopus (37) Google Scholar, D.M. T. J. L. S. Scheller J. the binding of interleukin 12 receptor beta1 and interleukin 23 receptor to Biol. PubMed Scopus (27) Google Scholar). for the of and within p40, or generated by by of with for of cytokines have been by of for Amino acids are to the with the signal of the cDNA murine or human IL-23 receptors was D.M. S. T. J. Grötzinger J. S. Scheller J. of and STAT3 in the of the interleukin 23 Biol. Chem. Full Text Full Text PDF PubMed Scopus (37) Google Scholar, M. J. N. T. C. C. Floss D.M. Scheller J. and murine interleukin 23 receptors are novel for a and and Biol. Chem. Full Text Full Text PDF PubMed Scopus (14) Google Scholar). Cloning of was in D.M. T. J. L. S. Scheller J. the binding of interleukin 12 receptor beta1 and interleukin 23 receptor to Biol. PubMed Scopus (27) Google Scholar). and as to the and to the To the cell with 5 in with and and for 3 in a of with or cytokines as from as The was to by the the of well and to 2 cell The signal from the is to the of in by of two and was are as For multiple by was was the of For of STAT3 and in cell for in was by with cytokines as and in 1 and with of cell was by protein to the of STAT3 and was by from cell and with or and STAT3 or For via in 1 and with for 1 on with the For cytokine variants receptors and In of was and The with the and by of by for The resulting to In of from cell or of cell by and to The in in and with the in in or in the with or in or in for 1 The and the for signal and variants to the was by which for the binding to was have been by For a was was in in composed of 12 and and and variants on a a of or was a of and The association in defined was in of and the was in of a binding on a from to with a and 2 in by of in 1 To the in the was cell molecular by of IL-12Rβ2 domains to and murine p40 the for protein and S. C.M. The for protein and 2015; PubMed Scopus Google Scholar). For of the IL-12 signaling a model of IL-12Rβ2 domains and the structure of D.M. for and Chem. PubMed Scopus Google the structure of the complex To the of in of and a model of was in data are within the J. A. A. J. Structural basis for the of IL-12 and IL-23 by Mol. Biol. PubMed Scopus Google Scholar, K.M. L. P.J. C. Garcia K.C. Structural basis for IL-12 and IL-23 receptor sharing reveals a for on T Full Text Full Text PDF PubMed Scopus Google Scholar). The that have of with the of have the and to the Molecular and with by the for and the of with from The is solely the of the and not the of the of and M. and M. and M. and J. S. and D. M. F. and J. M. T. L. D. and F. J. M. M. and Grötzinger J. M. M. J. S. and D. M. F. J. S. D. M. F. data D. M. F. D. M. F. D. M. F. with

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