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Science. 2015 Oct 23;350(6259):404-9. doi: 10.1126/science.aac5789. Epub 2015 Oct 8.

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

Author information

1
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA. Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
2
Center for Quantitative Biology, Peking-Tsinghua Joint Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, State Key Laboratory for Artificial Microstructures and Mesoscopic Physics, School of Physics, Peking University, Beijing 100871, China. Department of Cancer Immunology and Virology, Intel Parallel Computing Center for Structural Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
3
Department of Cancer Immunology and Virology, Intel Parallel Computing Center for Structural Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
4
Center for Nanoscale Systems, Harvard University, Cambridge, MA 02138, USA.
5
Center for Quantitative Biology, Peking-Tsinghua Joint Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, State Key Laboratory for Artificial Microstructures and Mesoscopic Physics, School of Physics, Peking University, Beijing 100871, China.
6
National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
7
Center for Quantitative Biology, Peking-Tsinghua Joint Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, State Key Laboratory for Artificial Microstructures and Mesoscopic Physics, School of Physics, Peking University, Beijing 100871, China. Department of Cancer Immunology and Virology, Intel Parallel Computing Center for Structural Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA. wu@crystal.harvard.edu youdong_mao@dfci.harvard.edu.
8
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA. Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA. wu@crystal.harvard.edu youdong_mao@dfci.harvard.edu.

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.

PMID:
26449474
PMCID:
PMC4640189
DOI:
10.1126/science.aac5789
[Indexed for MEDLINE]
Free PMC Article

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