Journal Article

PUBDB-2024-01586

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Structures of complete extracellular receptor assemblies mediated by IL-12 and IL-23

Bloch, Y. ; Felix, J. (Corresponding author)Extern* ; Merceron, R. ; Provost, M. ; Symakani, R. A. ; De Backer, R. ; Lambert, E. ; Mehdipour, A. R. ; Savvides, S. (Corresponding author)Extern*EMBL*

2024
Nature Publishing Group London [u.a.]

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Please use a persistent id in citations: doi:10.1038/s41594-023-01190-6

Abstract: Cell-surface receptor complexes mediated by pro-inflammatory interleukin (IL)-12 and IL-23, both validated therapeutic targets, are incompletely understood due to the lack of structural insights into their complete extracellular assemblies. Furthermore, there is a paucity of structural details describing the IL-12–receptor interaction interfaces, in contrast to IL-23–receptor complexes. Here we report structures of fully assembled mouse IL-12/human IL-23–receptor complexes comprising the complete extracellular segments of the cognate receptors determined by electron cryo-microscopy. The structures reveal key commonalities but also surprisingly diverse features. Most notably, whereas IL-12 and IL-23 both utilize a conspicuously presented aromatic residue on their α-subunit as a hotspot to interact with the N-terminal Ig domain of their high-affinity receptors, only IL-12 juxtaposes receptor domains proximal to the cell membrane. Collectively, our findings will help to complete our understanding of cytokine-mediated assemblies of tall cytokine receptors and will enable a cytokine-specific interrogation of IL-12/IL-23 signaling in physiology and disease.

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Contributing Institute(s):

1. EMBL-User (EMBL-User)

Research Program(s):

1. 6G3 - PETRA III (DESY) (POF4-6G3) (POF4-6G3)

Experiment(s):

1. PETRA Beamline P13 (PETRA III)
2. PETRA Beamline P14 (PETRA III)

Appears in the scientific report 2024

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