8SV1

Caspase-1 complex with interleukin-18

Summary for 8SV1

• Entry DOI: 10.2210/pdb8sv1/pdb
• EMDB information: 40781
• Descriptor: Caspase-1, Interleukin-18 (3 entities in total)
• Functional Keywords: innate immune, complex, hydrolase, immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 97433.10

Authors

Dong, Y.,Pascal, D.,Jon, K.,Wu, H. (deposition date: 2023-05-15, release date: 2024-05-08, Last modification date: 2025-05-28)

Primary citation

Dong, Y.,Bonin, J.P.,Devant, P.,Liang, Z.,Sever, A.I.M.,Mintseris, J.,Aramini, J.M.,Du, G.,Gygi, S.P.,Kagan, J.C.,Kay, L.E.,Wu, H.
Structural transitions enable interleukin-18 maturation and signaling.
Immunity, 57:1533-1548.e10, 2024

PubMed Abstract: Several interleukin-1 (IL-1) family members, including IL-1β and IL-18, require processing by inflammasome-associated caspases to unleash their activities. Here, we unveil, by cryoelectron microscopy (cryo-EM), two major conformations of the complex between caspase-1 and pro-IL-18. One conformation is similar to the complex of caspase-4 and pro-IL-18, with interactions at both the active site and an exosite (closed conformation), and the other only contains interactions at the active site (open conformation). Thus, pro-IL-18 recruitment and processing by caspase-1 is less dependent on the exosite than the active site, unlike caspase-4. Structure determination by nuclear magnetic resonance uncovers a compact fold of apo pro-IL-18, which is similar to caspase-1-bound pro-IL-18 but distinct from cleaved IL-18. Binding sites for IL-18 receptor and IL-18 binding protein are only formed upon conformational changes after pro-IL-18 cleavage. These studies show how pro-IL-18 is selected as a caspase-1 substrate, and why cleavage is necessary for its inflammatory activity.

PubMed: 38733997
DOI: 10.1016/j.immuni.2024.04.015

Experimental method

ELECTRON MICROSCOPY (3.5 Å)