TY - JOUR
T1 - Structural basis for flagellin-induced NAIP5 activation
AU - Paidimuddala, Bhaskar
AU - Cao, Jianhao
AU - Zhang, Liman
N1 - Publisher Copyright:
© 2023 American Association for the Advancement of Science. All rights reserved.
PY - 2023/12
Y1 - 2023/12
N2 - 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-D0C 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-D0N 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.
AB - 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-D0C 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-D0N 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.
UR - http://www.scopus.com/inward/record.url?scp=85179019577&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85179019577&partnerID=8YFLogxK
U2 - 10.1126/sciadv.adi8539
DO - 10.1126/sciadv.adi8539
M3 - Article
C2 - 38055825
AN - SCOPUS:85179019577
SN - 2375-2548
VL - 9
JO - Science Advances
JF - Science Advances
IS - 49
M1 - eadi8539
ER -