| First Author | Jones LL | Year | 2012 |
| Journal | Mol Immunol | Volume | 51 |
| Issue | 2 | Pages | 234-44 |
| PubMed ID | 22487722 | Mgi Jnum | J:184867 |
| Mgi Id | MGI:5426486 | Doi | 10.1016/j.molimm.2012.03.025 |
| Citation | Jones LL, et al. (2012) Distinct subunit pairing criteria within the heterodimeric IL-12 cytokine family. Mol Immunol 51(2):234-44 |
| abstractText | The heterodimeric IL-12 cytokine family is characterized by the sharing of three alpha (p19, p28, p35) and two beta (p40 and Ebi3) subunits, and includes IL-12 (p35/p40), IL-23 (p19/p40), IL-27 (p28/Ebi3) and IL-35 (p35/Ebi3). In this study, the dimerization interfaces of IL-12 family members were characterized, with emphasis on IL-35. Ebi3 and p35 subunits from human and mouse paired effectively with each other, indicating there is no species barrier to IL-35 dimerization and suggesting a conserved dimerization interface. Specific p35 residues that contribute to formation of the IL-12 interface were assessed for their contribution to the IL-35 interface, and candidate Ebi3 residues were screened for their contribution to both IL-27 and IL-35 interfaces. Several residues were identified as critical to the IL-12 or IL-27 interfaces. Conversely, no single mutation was identified that completely disrupts p35/Ebi3 pairing. Linear alanine scanning mutagenesis on both p35 and Ebi3 subunits was performed, focusing on residues that are conserved between the mouse and human proteins. Additionally, a structure-based alanine-scanning approach in which mutations were clustered based on proximitiy was performed on the p35 subunit. Both approaches suggest that IL-35 has distinct criteria for subunit pairing and is remarkabley less sensitive to structural perturbation than IL-12 and IL-27. Additionally, studies using a panel of anti-p35 and anti-Ebi3 antibodies indicate differential availability of epitopes within IL-12 family members that share these subunits, suggesting that IL-35 has distinct structural features, relative to IL-12 and IL-27. These results may be useful in future directed therapeutic targeting of IL-12 family members. |
