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Cryo-EM structure of the activated NAIP2-NLRC4 inflammasome reveals nucleated polymerization.


ABSTRACT: The NLR family apoptosis inhibitory proteins (NAIPs) bind conserved bacterial ligands, such as the bacterial rod protein PrgJ, and recruit NLR family CARD-containing protein 4 (NLRC4) as the inflammasome adapter to activate innate immunity. We found that the PrgJ-NAIP2-NLRC4 inflammasome is assembled into multisubunit disk-like structures through a unidirectional adenosine triphosphatase polymerization, primed with a single PrgJ-activated NAIP2 per disk. Cryo-electron microscopy (cryo-EM) reconstruction at subnanometer resolution revealed a ~90° hinge rotation accompanying NLRC4 activation. Unlike in the related heptameric Apaf-1 apoptosome, in which each subunit needs to be conformationally activated by its ligand before assembly, a single PrgJ-activated NAIP2 initiates NLRC4 polymerization in a domino-like reaction to promote the disk assembly. These insights reveal the mechanism of signal amplification in NAIP-NLRC4 inflammasomes.

SUBMITTER: Zhang L 

PROVIDER: S-EPMC4640189 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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Cryo-EM structure of the activated NAIP2-NLRC4 inflammasome reveals nucleated polymerization.

Zhang Liman L   Chen Shuobing S   Ruan Jianbin J   Wu Jiayi J   Tong Alexander B AB   Yin Qian Q   Li Yang Y   David Liron L   Lu Alvin A   Wang Wei Li WL   Marks Carolyn C   Ouyang Qi Q   Zhang Xinzheng X   Mao Youdong Y   Wu Hao H  

Science (New York, N.Y.) 20151008 6259


The NLR family apoptosis inhibitory proteins (NAIPs) bind conserved bacterial ligands, such as the bacterial rod protein PrgJ, and recruit NLR family CARD-containing protein 4 (NLRC4) as the inflammasome adapter to activate innate immunity. We found that the PrgJ-NAIP2-NLRC4 inflammasome is assembled into multisubunit disk-like structures through a unidirectional adenosine triphosphatase polymerization, primed with a single PrgJ-activated NAIP2 per disk. Cryo-electron microscopy (cryo-EM) recons  ...[more]

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