7crv
From Proteopedia
Crystal structure of rNLRP1-FIIND
Structural highlights
FunctionNL1A1_RAT Acts as the sensor component of the Nlrp1a inflammasome, which mediates inflammasome activation in response to various pathogen-associated signals, leading to subsequent pyroptosis (PubMed:33731929). Inflammasomes are supramolecular complexes that assemble in the cytosol in response to pathogens and other damage-associated signals and play critical roles in innate immunity and inflammation (By similarity). Acts as a recognition receptor (PRR): recognizes specific pathogens and other damage-associated signals, such as B.anthracis lethal toxin (LT) or Val-boroPro inhibitor, and mediates the formation of the inflammasome polymeric complex (PubMed:20502689, PubMed:31383852, PubMed:33731929). In response to pathogen-associated signals, the N-terminal part of Nlrp1a is degraded by the proteasome, releasing the cleaved C-terminal part of the protein (NACHT, LRR and PYD domains-containing protein 1a, C-terminus), which polymerizes to initiate the formation of the inflammasome complex: the inflammasome directly recruits pro-caspase-1 (proCASP1) independently of PYCARD/ASC and promotes caspase-1 (CASP1) activation, which subsequently cleaves and activates inflammatory cytokines IL1B and IL18 and gasdermin-D (GSDMD), leading to pyroptosis (By similarity). In the absence of GSDMD expression, the Nlrp1a inflammasome is able to recruit and activate CASP8, leading to activation of gasdermin-E (GSDME) (By similarity).[UniProtKB:Q2LKU9][UniProtKB:Q2LKW6][UniProtKB:Q9C000][1] [2] [3] Constitutes the precursor of the Nlrp1a inflammasome, which mediates autoproteolytic processing within the FIIND domain to generate the N-terminal and C-terminal parts, which are associated non-covalently in absence of pathogens and other damage-associated signals.[UniProtKB:Q9C000] Regulatory part that prevents formation of the Nlrp1a inflammasome: in absence of pathogens and other damage-associated signals, interacts with the C-terminal part of Nlrp1a (NACHT, LRR and PYD domains-containing protein 1a, C-terminus), preventing activation of the Nlrp1a inflammasome. In response to pathogen-associated signals, this part is ubiquitinated by the N-end rule pathway and degraded by the proteasome, releasing the cleaved C-terminal part of the protein, which polymerizes and forms the Nlrp1a inflammasome.[UniProtKB:Q9C000] Constitutes the active part of the Nlrp1a inflammasome (PubMed:33731929). In absence of pathogens and other damage-associated signals, interacts with the N-terminal part of Nlrp1a (NACHT, LRR and PYD domains-containing protein 1a, N-terminus), preventing activation of the Nlrp1a inflammasome. In response to pathogen-associated signals, the N-terminal part of Nlrp1a is degraded by the proteasome, releasing this form, which polymerizes to form the Nlrp1a inflammasome complex: the Nlrp1a inflammasome complex then directly recruits pro-caspase-1 (proCASP1) and promotes caspase-1 (CASP1) activation, leading to gasdermin-D (GSDMD) cleavage and subsequent pyroptosis.[UniProtKB:Q9C000][4] Publication Abstract from PubMedNucleotide-binding domain, leucine-rich repeat receptors (NLRs) mediate innate immunity by forming inflammasomes. Activation of the NLR protein NLRP1 requires autocleavage within its function-to-find domain (FIIND)(1-7). In resting cells, the dipeptidyl peptidases DPP8 and DPP9 interact with the FIIND of NLRP1 and suppress spontaneous NLRP1 activation(8,9); however, the mechanisms through which this occurs remain unknown. Here we present structural and biochemical evidence that full-length rat NLRP1 (rNLRP1) and rat DPP9 (rDPP9) form a 2:1 complex that contains an autoinhibited rNLRP1 molecule and an active UPA-CARD fragment of rNLRP1. The ZU5 domain is required not only for autoinhibition of rNLRP1 but also for assembly of the 2:1 complex. Formation of the complex prevents UPA-mediated higher-order oligomerization of UPA-CARD fragments and strengthens ZU5-mediated NLRP1 autoinhibition. Structure-guided biochemical and functional assays show that both NLRP1 binding and enzymatic activity are required for DPP9 to suppress NLRP1 in human cells. Together, our data reveal the mechanism of DPP9-mediated inhibition of NLRP1 and shed light on the activation of the NLRP1 inflammasome. Structural and biochemical mechanisms of NLRP1 inhibition by DPP9.,Huang M, Zhang X, Toh GA, Gong Q, Wang J, Han Z, Wu B, Zhong F, Chai J Nature. 2021 Apr;592(7856):773-777. doi: 10.1038/s41586-021-03320-w. Epub 2021 , Mar 17. PMID:33731929[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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