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TitleStructure and assembly of the human IL-12 signaling complex.
Journal, issue, pagesStructure, Vol. 32, Issue 10, Page 1640-11651.e5, Year 2024
Publish dateOct 3, 2024
AuthorsHuiqin Chen / Xiaofei Ge / Chun Li / Jianwei Zeng / Xinquan Wang /
PubMed AbstractInterleukin (IL)-12 is a heterodimeric pro-inflammatory cytokine. Our cryoelectron microscopy structure determination of human IL-12 in complex with IL-12Rβ1 and IL-12Rβ2 at a resolution of 3. ...Interleukin (IL)-12 is a heterodimeric pro-inflammatory cytokine. Our cryoelectron microscopy structure determination of human IL-12 in complex with IL-12Rβ1 and IL-12Rβ2 at a resolution of 3.75 Å reveals that IL-12Rβ2 primarily interacts with the IL-12p35 subunit via its N-terminal Ig-like domain, while IL-12Rβ1 binds to the p40 subunit with its N-terminal fibronectin III domain. This binding mode of IL-12 with its receptors is similar to that of IL-23 but shows notable differences with other cytokines. Through structural information and biochemical assays, we identified Y62, Y189, and K192 as key residues in IL-12p35, which bind to IL-12Rβ2 with high affinity and mediate IL-12 signal transduction. Furthermore, structural comparisons reveal two distinctive conformational states and structural plasticity of the heterodimeric interface in IL-12. As a result, our study advances our understanding of IL-12 signal initiation and opens up new opportunities for the engineering and therapeutic targeting of IL-12.
External linksStructure / PubMed:39111304
MethodsEM (single particle)
Resolution3.57 - 3.75 Å
Structure data

38609

8xrp

EMDB-38609, PDB-8xrp:
The Cryo-EM structure of IL-12, receptor subunit beta-1 and receptor subunit beta-2 complex
Method: EM (single particle) / Resolution: 3.75 Å

39311

8yi7

EMDB-39311, PDB-8yi7:
The Cryo-EM structure of IL-12, receptor subunit beta-1 and receptor subunit beta-2 complex, local refinement
Method: EM (single particle) / Resolution: 3.57 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

Source
  • homo sapiens (human)
KeywordsCYTOKINE / IL-12 / IL-12RB1 / IL-12RB2 / receptor complex

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