7rav | pdb_00007rav

Cryo-EM structure of the unliganded form of NLR family apoptosis inhibitory protein 5 (NAIP5)

spinqualitylabelsall models 7rav, resolution 3.30Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7rav is a 1 chain structure with sequence from Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.3Å Ligands: ATP Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function BIR1E_MOUSE Sensor component of the NLRC4 inflammasome that specifically recognizes and binds flagellin from pathogenic bacteria such as Legionella or Salmonella. Association of pathogenic bacteria proteins drives in turn drive assembly and activation of the NLRC4 inflammasome, promoting caspase-1 activation, cytokine production and macrophage pyroptosis. The NLRC4 inflammasome is activated as part of the innate immune response to a range of intracellular bacteria. The NLRC4 inflammasome senses Gram-negative bacteria such as L.pneumophila and P.aeruginosa, enteric pathogens S.typhimurium (Salmonella) and S.flexneri. Prevents motor-neuron apoptosis induced by a variety of signals. Publication Abstract from PubMed The nucleotide-binding domain (NBD), leucine rich repeat (LRR) domain containing protein family (NLR family) apoptosis inhibitory proteins (NAIPs) are cytosolic receptors that play critical roles in the host defense against bacterial infection. NAIPs interact with conserved bacterial ligands and activate the NLR family caspase recruitment domain containing protein 4 (NLRC4) to initiate the NAIP-NLRC4 inflammasome pathway. Here we found the process of NAIP activation is completely different from NLRC4. Our cryo-EM structure of unliganded mouse NAIP5 adopts an unprecedented wide-open conformation, with the nucleating surface fully exposed and accessible to recruit inactive NLRC4. Upon ligand binding, the winged helix domain (WHD) of NAIP5 undergoes roughly 20 degrees rotation to form a steric clash with the inactive NLRC4, which triggers the conformational change of NLRC4 from inactive to active state. We also show the rotation of WHD places the 17-18 loop at a position that directly bind the active NLRC4 and stabilize the NAIP5-NLRC4 complex. Overall, these data provide structural mechanisms of inactive NAIP5, the process of NAIP5 activation and NAIP-dependent NLRC4 activation. Mechanism of NAIP-NLRC4 inflammasome activation revealed by cryo-EM structure of unliganded NAIP5.,Paidimuddala B, Cao J, Nash G, Xie Q, Wu H, Zhang L Nat Struct Mol Biol. 2023 Feb;30(2):159-166. doi: 10.1038/s41594-022-00889-2. , Epub 2023 Jan 5. PMID:36604500 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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