Crystal structure of NLRC4 reveals its autoinhibition mechanism

Zehan Hu, Chuangye Yan, Peiyuan Liu, Zhiwei Huang, Rui Ma, Chenlu Zhang, Ruiyong Wang, Yueteng Zhang, Fabio Martinon, Di Miao, Haiteng Deng, Jiawei Wang, Junbiao Chang, Jijie Chai

Research output: Contribution to journalArticle

177 Citations (Scopus)

Abstract

Nucleotide-binding and oligomerization domain-like receptor (NLR) proteins oligomerize into multiprotein complexes termed inflammasomes when activated. Their autoinhibition mechanism remains poorly defined. Here, we report the crystal structure of mouse NLRC4 in a closed form. The adenosine diphosphate-mediated interaction between the central nucleotide-binding domain (NBD) and the winged-helix domain (WHD) was critical for stabilizing the closed conformation of NLRC4. The helical domain HD2 repressively contacted a conserved and functionally important α-helix of the NBD. The C-terminal leucine-rich repeat (LRR) domain is positioned to sterically occlude one side of the NBD domain and consequently sequester NLRC4 in a monomeric state. Disruption of ADP-mediated NBD-WHD or NBD-HD2/NBD-LRR interactions resulted in constitutive activation of NLRC4. Together, our data reveal the NBD-organized cooperative autoinhibition mechanism of NLRC4 and provide insight into its activation.

Original languageEnglish (US)
Pages (from-to)172-175
Number of pages4
JournalScience
Volume341
Issue number6142
DOIs
StatePublished - Jan 1 2013
Externally publishedYes

Fingerprint

Nucleotides
Leucine
Adenosine Diphosphate
Inflammasomes
Multiprotein Complexes

ASJC Scopus subject areas

  • General

Cite this

Hu, Z., Yan, C., Liu, P., Huang, Z., Ma, R., Zhang, C., ... Chai, J. (2013). Crystal structure of NLRC4 reveals its autoinhibition mechanism. Science, 341(6142), 172-175. https://doi.org/10.1126/science.1236381

Crystal structure of NLRC4 reveals its autoinhibition mechanism. / Hu, Zehan; Yan, Chuangye; Liu, Peiyuan; Huang, Zhiwei; Ma, Rui; Zhang, Chenlu; Wang, Ruiyong; Zhang, Yueteng; Martinon, Fabio; Miao, Di; Deng, Haiteng; Wang, Jiawei; Chang, Junbiao; Chai, Jijie.

In: Science, Vol. 341, No. 6142, 01.01.2013, p. 172-175.

Research output: Contribution to journalArticle

Hu, Z, Yan, C, Liu, P, Huang, Z, Ma, R, Zhang, C, Wang, R, Zhang, Y, Martinon, F, Miao, D, Deng, H, Wang, J, Chang, J & Chai, J 2013, 'Crystal structure of NLRC4 reveals its autoinhibition mechanism', Science, vol. 341, no. 6142, pp. 172-175. https://doi.org/10.1126/science.1236381
Hu Z, Yan C, Liu P, Huang Z, Ma R, Zhang C et al. Crystal structure of NLRC4 reveals its autoinhibition mechanism. Science. 2013 Jan 1;341(6142):172-175. https://doi.org/10.1126/science.1236381
Hu, Zehan ; Yan, Chuangye ; Liu, Peiyuan ; Huang, Zhiwei ; Ma, Rui ; Zhang, Chenlu ; Wang, Ruiyong ; Zhang, Yueteng ; Martinon, Fabio ; Miao, Di ; Deng, Haiteng ; Wang, Jiawei ; Chang, Junbiao ; Chai, Jijie. / Crystal structure of NLRC4 reveals its autoinhibition mechanism. In: Science. 2013 ; Vol. 341, No. 6142. pp. 172-175.
@article{1f4794f91b414b65b249a1bd1ee273d2,
title = "Crystal structure of NLRC4 reveals its autoinhibition mechanism",
abstract = "Nucleotide-binding and oligomerization domain-like receptor (NLR) proteins oligomerize into multiprotein complexes termed inflammasomes when activated. Their autoinhibition mechanism remains poorly defined. Here, we report the crystal structure of mouse NLRC4 in a closed form. The adenosine diphosphate-mediated interaction between the central nucleotide-binding domain (NBD) and the winged-helix domain (WHD) was critical for stabilizing the closed conformation of NLRC4. The helical domain HD2 repressively contacted a conserved and functionally important α-helix of the NBD. The C-terminal leucine-rich repeat (LRR) domain is positioned to sterically occlude one side of the NBD domain and consequently sequester NLRC4 in a monomeric state. Disruption of ADP-mediated NBD-WHD or NBD-HD2/NBD-LRR interactions resulted in constitutive activation of NLRC4. Together, our data reveal the NBD-organized cooperative autoinhibition mechanism of NLRC4 and provide insight into its activation.",
author = "Zehan Hu and Chuangye Yan and Peiyuan Liu and Zhiwei Huang and Rui Ma and Chenlu Zhang and Ruiyong Wang and Yueteng Zhang and Fabio Martinon and Di Miao and Haiteng Deng and Jiawei Wang and Junbiao Chang and Jijie Chai",
year = "2013",
month = "1",
day = "1",
doi = "10.1126/science.1236381",
language = "English (US)",
volume = "341",
pages = "172--175",
journal = "Science",
issn = "0036-8075",
publisher = "American Association for the Advancement of Science",
number = "6142",

}

TY - JOUR

T1 - Crystal structure of NLRC4 reveals its autoinhibition mechanism

AU - Hu, Zehan

AU - Yan, Chuangye

AU - Liu, Peiyuan

AU - Huang, Zhiwei

AU - Ma, Rui

AU - Zhang, Chenlu

AU - Wang, Ruiyong

AU - Zhang, Yueteng

AU - Martinon, Fabio

AU - Miao, Di

AU - Deng, Haiteng

AU - Wang, Jiawei

AU - Chang, Junbiao

AU - Chai, Jijie

PY - 2013/1/1

Y1 - 2013/1/1

N2 - Nucleotide-binding and oligomerization domain-like receptor (NLR) proteins oligomerize into multiprotein complexes termed inflammasomes when activated. Their autoinhibition mechanism remains poorly defined. Here, we report the crystal structure of mouse NLRC4 in a closed form. The adenosine diphosphate-mediated interaction between the central nucleotide-binding domain (NBD) and the winged-helix domain (WHD) was critical for stabilizing the closed conformation of NLRC4. The helical domain HD2 repressively contacted a conserved and functionally important α-helix of the NBD. The C-terminal leucine-rich repeat (LRR) domain is positioned to sterically occlude one side of the NBD domain and consequently sequester NLRC4 in a monomeric state. Disruption of ADP-mediated NBD-WHD or NBD-HD2/NBD-LRR interactions resulted in constitutive activation of NLRC4. Together, our data reveal the NBD-organized cooperative autoinhibition mechanism of NLRC4 and provide insight into its activation.

AB - Nucleotide-binding and oligomerization domain-like receptor (NLR) proteins oligomerize into multiprotein complexes termed inflammasomes when activated. Their autoinhibition mechanism remains poorly defined. Here, we report the crystal structure of mouse NLRC4 in a closed form. The adenosine diphosphate-mediated interaction between the central nucleotide-binding domain (NBD) and the winged-helix domain (WHD) was critical for stabilizing the closed conformation of NLRC4. The helical domain HD2 repressively contacted a conserved and functionally important α-helix of the NBD. The C-terminal leucine-rich repeat (LRR) domain is positioned to sterically occlude one side of the NBD domain and consequently sequester NLRC4 in a monomeric state. Disruption of ADP-mediated NBD-WHD or NBD-HD2/NBD-LRR interactions resulted in constitutive activation of NLRC4. Together, our data reveal the NBD-organized cooperative autoinhibition mechanism of NLRC4 and provide insight into its activation.

UR - http://www.scopus.com/inward/record.url?scp=84880280093&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84880280093&partnerID=8YFLogxK

U2 - 10.1126/science.1236381

DO - 10.1126/science.1236381

M3 - Article

C2 - 23765277

AN - SCOPUS:84880280093

VL - 341

SP - 172

EP - 175

JO - Science

JF - Science

SN - 0036-8075

IS - 6142

ER -