6KN0

caspase-1 P20/P10 C285A in complex with human GSDMD-C domain

Summary for 6KN0

• Entry DOI: 10.2210/pdb6kn0/pdb
• Descriptor: Caspase-1, Gasdermin-D (3 entities in total)
• Functional Keywords: pyroptosis, immune system
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 6
• Total formula weight: 100575.40

Authors

Ding, J.,Sun, Q. (deposition date: 2019-08-02, release date: 2020-03-11, Last modification date: 2023-11-22)

Primary citation

Wang, K.,Sun, Q.,Zhong, X.,Zeng, M.,Zeng, H.,Shi, X.,Li, Z.,Wang, Y.,Zhao, Q.,Shao, F.,Ding, J.
Structural Mechanism for GSDMD Targeting by Autoprocessed Caspases in Pyroptosis.
Cell, 180:941-, 2020

PubMed Abstract: The pyroptosis execution protein GSDMD is cleaved by inflammasome-activated caspase-1 and LPS-activated caspase-11/4/5. The cleavage unmasks the pore-forming domain from GSDMD-C-terminal domain. How the caspases recognize GSDMD and its connection with caspase activation are unknown. Here, we show site-specific caspase-4/11 autoprocessing, generating a p10 product, is required and sufficient for cleaving GSDMD and inducing pyroptosis. The p10-form autoprocessed caspase-4/11 binds the GSDMD-C domain with a high affinity. Structural comparison of autoprocessed and unprocessed capase-11 identifies a β sheet induced by the autoprocessing. In caspase-4/11-GSDMD-C complex crystal structures, the β sheet organizes a hydrophobic GSDMD-binding interface that is only possible for p10-form caspase-4/11. The binding promotes dimerization-mediated caspase activation, rendering a cleavage independently of the cleavage-site tetrapeptide sequence. Crystal structure of caspase-1-GSDMD-C complex shows a similar GSDMD-recognition mode. Our study reveals an unprecedented substrate-targeting mechanism for caspases. The hydrophobic interface suggests an additional space for developing inhibitors specific for pyroptotic caspases.

PubMed: 32109412
DOI: 10.1016/j.cell.2020.02.002

Experimental method

X-RAY DIFFRACTION (2.793 Å)