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DOE OSTI · 2471637

Structural basis for flagellin-induced NAIP5 activation

Paidimuddala, Bhaskar·Cao, Jianhao·Zhang, Liman
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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.

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60 APPLIED LIFE SCIENCESScience & Technology

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Paidimuddala, Bhaskar, Cao, Jianhao, Zhang, Liman. 2023-12-06. Structural basis for flagellin-induced NAIP5 activation. https://doi.org/10.1126/sciadv.adi8539

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