7WR0

P32 of caspase-4 C258A mutant

Summary for 7WR0

• Entry DOI: 10.2210/pdb7wr0/pdb
• Descriptor: Caspase-4 (1 entity in total)
• Functional Keywords: protease, mutant, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 32095.43

Authors

Hou, Y.J.,Zeng, H.,Shao, F.,Ding, J. (deposition date: 2022-01-26, release date: 2023-01-25, Last modification date: 2023-11-29)

Primary citation

Hou, Y.,Zeng, H.,Li, Z.,Feng, N.,Meng, F.,Xu, Y.,Li, L.,Shao, F.,Ding, J.
Structural mechanisms of calmodulin activation of Shigella effector OspC3 to ADP-riboxanate caspase-4/11 and block pyroptosis.
Nat.Struct.Mol.Biol., 30:261-272, 2023

PubMed Abstract: The caspase-4/11-GSDMD pyroptosis axis recognizes cytosolic lipopolysaccharide for antibacterial defenses. Shigella flexneri employs an OspC3 effector to block pyroptosis by catalyzing NAD-dependent arginine ADP-riboxanation of caspase-4/11. Here, we identify Ca-free calmodulin (CaM) that binds and stimulates OspC3 ADP-riboxanase activity. Crystal structures of OspC3-CaM and OspC3-caspase-4 binary complexes reveal unique CaM binding to an OspC3 N-terminal domain featuring an ADP-ribosyltransferase-like fold and specific recognition of caspase-4 by an OspC3 ankryin repeat domain, respectively. CaM-OspC3-caspase-4 ternary complex structures show that NAD binding reorganizes the catalytic pocket, in which D231 and D177 activate the substrate arginine for initial ADP-ribosylation and ribosyl 2'-OH in the ADP-ribosylated arginine, respectively, for subsequent deamination. We also determine structures of unmodified and OspC3-ADP-riboxanated caspase-4. Mechanisms derived from this series of structures covering the entire process of OspC3 action are supported by biochemical analyses in vitro and functional validation in S. flexneri-infected mice.

PubMed: 36624349
DOI: 10.1038/s41594-022-00888-3

Experimental method

X-RAY DIFFRACTION (2.8 Å)