Download MendeleyStructural Activation of Pro-inflammatory Human Cytokine IL-23 by Cognate IL-23 Receptor Enables Recruitment of the Shared Receptor IL-12R beta 1.
Bloch, Y., Bouchareychas, L., Merceron, R., Skladanowska, K., Van den Bossche, L., Detry, S., Govindarajan, S., Elewaut, D., Haerynck, F., Dullaers, M., Adamopoulos, I.E., Savvides, S.N.(2018) Immunity 48: 45-58.e6
- PubMed: 29287995
- DOI: https://doi.org/10.1016/j.immuni.2017.12.008
- Primary Citation of Related Structures:
5MXA, 5MZV, 5N2K, 5NJD - PubMed Abstract:
Interleukin-23 (IL-23), an IL-12 family cytokine, plays pivotal roles in pro-inflammatory T helper 17 cell responses?linked to autoimmune and inflammatory diseases. Despite intense therapeutic targeting, structural and mechanistic insights into receptor complexes mediated by IL-23, and by IL-12 family members in general, have remained elusive. We determined a crystal structure of human IL-23 in complex with its cognate receptor, IL-23R, and revealed that IL-23R bound to IL-23 exclusively via its N-terminal immunoglobulin domain. The structural and functional hotspot of this interaction partially restructured the helical IL-23p19 subunit of IL-23 and?restrained its IL-12p40 subunit to cooperatively bind the shared receptor IL-12R¦Â1 with high affinity. Together with structural insights from the interaction of IL-23 with the inhibitory antibody briakinumab and by leveraging additional IL-23:antibody complexes, we propose a mechanistic paradigm for IL-23 and IL-12 whereby cognate receptor binding to the helical cytokine subunits primes recruitment of the shared receptors via the IL-12p40 subunit.
Organizational Affiliation:
Laboratory for Protein Biochemistry and Biomolecular Engineering, Department of Biochemistry and Microbiology, Ghent University, 9052 Ghent, Belgium; VIB-UGent Center for Inflammation Research, 9052 Ghent, Belgium.
