Journal Article

Structural basis for the oligomerization-mediated regulation of NLRP3 inflammasome activation

Zhang, Zhikuan, Hirama, Chie, Shimizu, Toshiyuki, Kamitsukasa, Yukie, Ohto, Umeharu, Maekawa, Sakiko, Murakami, Karin, Ishida, Hanako

2022

Overview

The nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain containing 3 (NLRP3) responds to a vast variety of stimuli, and activated NLRP3 forms an inflammasome, which in turn is associated with conditions such as atherosclerosis, Alzheimer’s disease, and diabetes. A multilayered regulatory mechanism ensures proper NLRP3 inflammasome activation, although the structural basis for this process remains unclear. This study aimed to investigate the cryo-electron microscopy structure of the dodecameric form of full-length NLRP3 bound to the clinically relevant NLRP3-specific inhibitor MCC950. The inhibitor binds to the cavity distinct from the nucleotide binding site in the NACHT domain and stabilizes the closed conformation of NLRP3. The barrel-shaped dodecamer composed of the inactive form of NLRP3 is formed mainly through LRR–LRR interactions on the lateral side, and the highly positively charged top and bottom sides composed of NACHT domains provide a scaffold for membrane association. The cryo-electron microscopy structure suggests that oligomerization of NLRP3 is necessary for its membrane association; it is subsequently disrupted for activation, hence serving as a key player in controlling the spatiotemporal NLRP3 inflammasome activation. These findings are expected to contribute to the development of drugs targeting NLRP3 in future.

• Publisher: National Academy of Sciences
• Subject: Alzheimer's disease / Animals / Arteriosclerosis / Atherosclerosis / Binding Sites / Biological Sciences / Conformation / Cryoelectron Microscopy / Diabetes mellitus / Domains / Drug delivery / Drug development / Electron microscopy / Immunology and Inflammation / Inflammasomes / Inflammasomes - metabolism / Inhibitors / Membranes / Mice / Microscopy / Models, Molecular / Mutation / Neurodegenerative diseases / NLR Family, Pyrin Domain-Containing 3 Protein - antagonists & inhibitors / NLR Family, Pyrin Domain-Containing 3 Protein - chemistry / NLR Family, Pyrin Domain-Containing 3 Protein - metabolism / Nucleotides / Oligomerization / Protein Binding / Protein Conformation / Protein Multimerization / Pyrin protein / Regulatory mechanisms (biology) / Structure-Activity Relationship / Transmission electron microscopy