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Structural basis for flagellin-induced NAIP5 activation

Year: 2023
Type: article
Abstract: The NAIP (NLR family apoptosis inhibitory protein)/NLRC4 (NLR family CARD containing protein 4) inflammasome senses Gram-negative bacterial ligand. In the ligand-bound state, the winged helix domain of NAIP forms a steric clash with NLRC4 to open it up. However, how ligand binding activates NAIP is less clear. Here, we investigated the dynamics of the ligand-binding region of inactive NAIP5 and solved the cryo-EM structure of NAIP5 in complex with its specific ligand, FliC from flagellin, at 2.9-Å resolution. The structure revealed a “trap and lock” mechanism in FliC recognition, whereby FliC-D0 C is first trapped by the hydrophobic pocket of NAIP5, then locked in the binding site by ID (insertion domain) and C-terminal tail of NAIP5. The FliC-D0 N domain further inserts into ID to stabilize the complex. According to this mechanism, FliC triggers the conformational change of NAIP5 by bringing multiple flexible domains together.
DOI: 10.1126/sciadv.adi8539
Language: English
Open Access status: gold
Estimated APC paid: $4,500
Funders: U.S. Department of Energy, Oregon Health and Science University, National Institutes of Health, Office of Science, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, Biological and Environmental Research
Awards: G3508161151, G5718375046, Pacific Northwest Center for Cryo-EM, G6780141363, G7562546725, G7673727097, G7913850483, Elucidating the Structural Mechanisms of NAIP Receptors in Bacterial Detection and Inflammasome Activation
OpenAlex ID: W4389371417
FWCI: 1.261
Cites: 35
Cited by: 17
Related to: 10