2021
DOI: 10.1101/2021.08.26.457804
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Cryo-ET of a human GBP coatomer governing cell-autonomous innate immunity to infection

Abstract: All living organisms deploy cell-autonomous defenses to combat infection. In plants and animals, these activities generate large supramolecular complexes that recruit immune proteins for protection. Here, we solve the native structure of a massive antimicrobial complex generated by polymerization of 30,000 human guanylate-binding proteins (GBPs) over the entire surface of virulent bacteria. Construction of this giant nanomachine takes ~1-3 minutes, remains stable for hours, and acts as a cytokine and cell deat… Show more

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Cited by 15 publications
(14 citation statements)
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“…Alanine-scanning mutagenesis of the three arginines in α 13 helix of hGBP1 ablated the farnesylated protein’s ability to bind to bacterial outer membranes. 55 The mGBP2 does not have repeated lysine or arginine residues in α 13 directly before the CaaX motif, only a single lysine residue (K585), which one can expect to help in membrane binding together with the longer geranylgeranyl lipid anchor compared to the farnesyl group in hGBP1. The sequence 567 KRK 569 in mGBP7 is directly before the CT tail, which was demonstrated to be essential for membrane binding.…”
Section: Resultsmentioning
confidence: 99%
“…Alanine-scanning mutagenesis of the three arginines in α 13 helix of hGBP1 ablated the farnesylated protein’s ability to bind to bacterial outer membranes. 55 The mGBP2 does not have repeated lysine or arginine residues in α 13 directly before the CaaX motif, only a single lysine residue (K585), which one can expect to help in membrane binding together with the longer geranylgeranyl lipid anchor compared to the farnesyl group in hGBP1. The sequence 567 KRK 569 in mGBP7 is directly before the CT tail, which was demonstrated to be essential for membrane binding.…”
Section: Resultsmentioning
confidence: 99%
“…The tip of membrane tubules forms a region of maximum curvature, which could facilitate access to the membrane-embedded acyl chains of lipid A otherwise shielded by the dense oligosaccharide chains of LPS and therefore inaccessible to the ligand-binding CARD domain of capase-4. A recent study reporting tomographic data on GBP1 coatomer suggested the coat consists of GBP1 monomers (48), which is inconsistent with the GBP1 dimer units observed in our cryo-EM and cryo-ET data reported here and with previous biochemical studies that established homodimer formation as a prerequisite for membrane association of GBP1 (34). Interestingly, LPS and GBP1-dependent retrieval of caspase-4 in cellular pull-downs requires GDP-AlFx (21), confirming the functional relevance of the GBP1 dimer conformation in the membrane-bound oligomers under conditions mimicking the transition-state of GTP hydrolysis.…”
Section: Discussionmentioning
confidence: 99%
“…Consistent with this hypothesis, Zhu et al found that GBP1 enhances the release of labeled LPS from intracellular S . Typhimurium using a fluorescent microscopy-based assay (18). These observations suggest that GBP1 mediates LPS release from intracellular bacteria into the host cell cytosol; whether the liberated LPS is in clusters or within OMVs will be the subject of future studies.…”
Section: Discussionmentioning
confidence: 99%
“…GBP1 is the first to bind via direct interactions with LPS (16,17). Thousands of molecules of GBP1 intercalate into the outer bacterial membrane to form a stable coat, referred to as the GBP1 microcapsule or coatomer (16,18). Subsequently, GBP2, GBP3, and GBP4 (19)(20)(21), and in some cases, CASP4 (10,16,17,22) are recruited to the bacteria.…”
Section: Introductionmentioning
confidence: 99%