38ww

Crystal structure of the CFTR inhibitory factor Cif with the S179G mutation

spinqualitylabelsall models 38ww, resolution 1.70Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 38ww is a 4 chain structure with sequence from Pseudomonas aeruginosa UCBPP-PA14. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.7Å Ligands: CA Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function CIF_PSEAB Virulence factor that impairs the host airway defenses and may play an important role in the early colonization of the lung (PubMed:18458065, PubMed:20118260, PubMed:28982736). It decreases mucociliary transport and hinders bacterial clearance from the lung, likely increasing the severity or duration of the infection (PubMed:28982736). Cif decreases the apical membrane abundance of host cystic fibrosis transmembrane conductance regulator (CFTR), which plays an important role in airway mucociliary defense, and reduces the CFTR-mediated chloride ion secretion in human airway epithelial cells and kidney cells (PubMed:17502391, PubMed:21455491). It alters the intracellular trafficking of CFTR, and redirects CFTR from recycling endosomes to the lysosomal degradative pathway (PubMed:21455491). Cif acts by enhancing the interaction of the host cell deubiquitinating enzyme USP10 with the Ras GTPase-activating protein-binding protein 1 (G3BP1), which inhibits the ability of USP10 to interact with, and deubiquitinate CFTR (PubMed:21455491). Inactivation of USP10 facilitates the lysosome-mediated degradation of the CFTR secretory chloride channel, which reduces mucociliary clearance of respiratory pathogens by human airway epithelial cells (PubMed:21455491). It reduces mucociliary transport (MCT) in vitro and the clearance of P.aeruginosa from the host in vivo (PubMed:28982736). Cif also reduces the apical membrane abundance of the host ATP-dependent translocase ABCB1 (P-glycoprotein 1, MDR1) in kidney, intestine and airway epithelial cells (PubMed:18650266). In addition, it reduces the protein abundance of the antigen peptide transporter 1 (TAP1), but not protein abundance of TAP2 (PubMed:24247241). Reducing USP10 deubiquitinating activity leads to increased ubiquitination and proteasomal degradation of TAP1, which reduces TAP-mediated transport of peptides into the endoplasmic reticulum and subsequent MHC class I-mediated viral and bacterial antigen presentation at the host cell surface (PubMed:24247241). Retrograde trafficking of Cif to the endoplasmic reticulum is required for the Cif-mediated reduction in TAP1 (PubMed:24247241). In contrast, Cif has no effect on the membrane abundance of some other ABC transporters such as ABCC1 (MRP1) and ABCC2 (MRP2) (PubMed:18650266). Cif shows epoxide hydrolase activity (PubMed:17502391, PubMed:18458065, PubMed:20118260, PubMed:21933119, PubMed:26136396, PubMed:26752215, PubMed:27980032, PubMed:28392259). The host epithelial-derived 14,15-epoxyeicosatrienoic acid (14,15-EET) was identified as an endogenous substrate (PubMed:27980032). 14,15-EET plays a particularly critical role as a paracrine stimulus for the production by neutrophils of the proresolving lipid mediator 15-epi LXA(4), which plays a critical role in limiting neutrophil activation and tissue inflammation (PubMed:27980032). Cif hydrolyzes 14,15-EET produced in response to inflammation into its cognate diol, indirectly eliminating the production of the proresolving lipid 15-epi LXA(4) by host neutrophils, which promotes sustained airway inflammation (PubMed:27980032). The epoxide hydrolase activity of Cif is also strictly required for its effects on CFTR, suggesting the existence of an epoxide signal involved in the deubiquitination and post-endocytic recycling of CFTR (PubMed:20118260, PubMed:26136396). The active site can accommodate a range of potential physiological epoxide substrates, suggesting that Cif can target and perturb key host immune signals (PubMed:28392259). It can degrade in vitro the xenobiotic substrate epoxide epibromohydrin (EBH) to its vicinal diol, 3-bromo-1,2-propanediol (PubMed:18458065, PubMed:20118260, PubMed:21933119, PubMed:26136396, PubMed:26752215). It also acts on the epoxide hydrolase synthetic substrate (S)-NEPC in a concentration-dependent manner (PubMed:17502391). Also shows activity against cis-stilbene oxide (CSO) (PubMed:20118260). Does not exhibit haloacetate dehalogenase (HAD) or haloalkane dehalogenase (HLD) activity against standard substrates (PubMed:20118260).

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