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Myeloid Innate Signaling Pathway Regulation by MALT1 Paracaspase Activity

Myeloid Innate Signaling Pathway Regulation by MALT1 Paracaspase Activity

Published on: January 7, 2019

Structural transitions enable interleukin-18 maturation and signaling

Ying Dong¹, Jeffrey P Bonin², Pascal Devant³

¹Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, USA.

|May 11, 2024

Summary

Caspase-1 processes pro-IL-18 differently than caspase-4, utilizing its active site more than an exosite. This cleavage is essential for activating IL-18

Area of Science:

Molecular biology
Structural biology
Immunology

Background:

Interleukin-1 (IL-1) family members, such as IL-1β and IL-18, require activation by inflammasome-associated caspases.
Understanding the molecular mechanisms of caspase-mediated substrate processing is crucial for comprehending inflammatory pathways.

Purpose of the Study:

To elucidate the structural basis of pro-IL-18 recognition and processing by caspase-1.
To compare the interaction modes of caspase-1 with pro-IL-18 against those of caspase-4 with pro-IL-18.
To investigate the conformational changes in pro-IL-18 upon caspase-1 binding and cleavage.

Main Methods:

Cryoelectron microscopy (cryo-EM) was employed to determine the structures of caspase-1/pro-IL-18 complexes.
Nuclear magnetic resonance (NMR) spectroscopy was used to study the structure of apo pro-IL-18 and its conformational states.

Main Results:

Two distinct conformations of the caspase-1/pro-IL-18 complex were identified: a closed conformation (active site and exosite interactions) and an open conformation (active site interactions only).
Pro-IL-18 recruitment and processing by caspase-1 show a greater dependence on the active site compared to the exosite, differing from caspase-4.
Apo pro-IL-18 adopts a compact fold, which is maintained upon caspase-1 binding but altered after cleavage, revealing distinct structures for mature IL-18.
Binding sites for the IL-18 receptor and IL-18 binding protein are formed only after pro-IL-18 cleavage, indicating a requirement for conformational changes.

Conclusions:

The structural studies reveal the specific mechanisms by which caspase-1 selects and processes pro-IL-18.
The findings highlight the differential utilization of active site and exosite interactions by caspases in substrate recognition.
Cleavage by caspase-1 is demonstrated to be a critical step for inducing conformational changes in pro-IL-18, thereby enabling its inflammatory activity and receptor binding.

Keywords:

IL-18 NMR caspase-1 conformational change cryo-EM cytokine cleavage inflammatory activity pro-IL-18

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