8FW9

Cryo-EM structure of full-length human NLRC4 inflammasome with C12 symmetry

Summary for 8FW9

• Entry DOI: 10.2210/pdb8fw9/pdb
• EMDB information: 29498
• Descriptor: NLR family CARD domain-containing protein 4 (1 entity in total)
• Functional Keywords: nlrc4, naip, inflammasome, immune system
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 3
• Total formula weight: 351082.97

Authors

Matico, R.E.,Yu, X.,Miller, R.,Somani, S.,Ricketts, M.D.,Kumar, N.,Steele, R.A.,Medley, Q.,Berger, S.,Faustin, B.,Sharma, S. (deposition date: 2023-01-20, release date: 2024-01-03, Last modification date: 2024-01-31)

Primary citation

Matico, R.E.,Yu, X.,Miller, R.,Somani, S.,Ricketts, M.D.,Kumar, N.,Steele, R.A.,Medley, Q.,Berger, S.,Faustin, B.,Sharma, S.
Structural basis of the human NAIP/NLRC4 inflammasome assembly and pathogen sensing.
Nat.Struct.Mol.Biol., 31:82-91, 2024

PubMed Abstract: The NLR family caspase activation and recruitment domain-containing 4 (NLRC4) inflammasome is a critical cytosolic innate immune machine formed upon the direct sensing of bacterial infection and in response to cell stress during sterile chronic inflammation. Despite its major role in instigating the subsequent host immune response, a more complete understanding of the molecular events in the formation of the NLRC4 inflammasome in humans is lacking. Here we identify Bacillus thailandensis type III secretion system needle protein (Needle) as a potent trigger of the human NLR family apoptosis inhibitory protein (NAIP)/NLRC4 inflammasome complex formation and determine its structural features by cryogenic electron microscopy. We also provide a detailed understanding of how type III secretion system pathogen components are sensed by human NAIP to form a cascade of NLRC4 protomer through a critical lasso-like motif, a 'lock-key' activation model and large structural rearrangement, ultimately forming the full human NLRC4 inflammasome. These results shed light on key regulatory mechanisms specific to the NLRC4 inflammasome assembly, and the innate immune modalities of pathogen sensing in humans.

PubMed: 38177670
DOI: 10.1038/s41594-023-01143-z

Experimental method

ELECTRON MICROSCOPY (4.46 Å)