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dc.contributor.authorSharma, Stuti
dc.contributor.authorZhou, Ruoyu
dc.contributor.authorWan, Li
dc.contributor.authorSong, KangKang
dc.contributor.authorXu, Chen
dc.contributor.authorLi, Yanyan
dc.contributor.authorLiao, Maofu
dc.date2022-08-11T08:08:27.000
dc.date.accessioned2022-08-23T15:55:43Z
dc.date.available2022-08-23T15:55:43Z
dc.date.issued2021-04-08
dc.date.submitted2021-06-28
dc.identifier.citation<p>bioRxiv 2021.04.06.438740; doi: https://doi.org/10.1101/2021.04.06.438740. <a href="https://doi.org/10.1101/2021.04.06.438740" target="_blank" title="view preprint in bioRxiv">Link to preprint on bioRxiv.</a></p>
dc.identifier.doi10.1101/2021.04.06.438740
dc.identifier.urihttp://hdl.handle.net/20.500.14038/29817
dc.description<p>This article is a preprint. Preprints are preliminary reports of work that have not been certified by peer review.</p>
dc.description.abstractPresent in all bacteria, lipoproteins are central in bacterial growth and antibiotic resistance. These proteins use lipid acyl chains attached to the N-terminal cysteine residue to anchor on the outer surface of cytoplasmic membrane. In Gram-negative bacteria, many lipoproteins are transported to the outer membrane (OM), a process dependent on the ATP-binding cassette (ABC) transporter LolCDE which extracts the OM-targeted lipoproteins from the cytoplasmic membrane for subsequent trafficking across the periplasm. Lipid-anchored proteins pose a unique challenge for transport machinery as they have both hydrophobic lipid moieties and soluble protein component, and the underlying mechanism is poorly understood. Here we determined the cryo-EM structures of nanodisc-embedded LolCDE in the nucleotide-free and nucleotide-bound states at 3.8-Å and 3.5-Å resolution, respectively. The structural analyses, together with biochemical and mutagenesis studies, uncover how LolCDE specifically recognizes its substrate by establishing multiple interactions with the lipid and N-terminal peptide moieties of the lipoprotein, and identify the amide-linked acyl chain as the key element for LolCDE interaction. Upon nucleotide binding, the transmembrane helices and the periplasmic domains of LolCDE undergo large-scale, asymmetric movements, resulting in extrusion of the captured lipoprotein. Comparison of LolCDE and MacB reveals the conserved mechanism of type VII ABC transporters and emphasizes the unique properties of LolCDE as a molecule extruder of triacylated lipoproteins.
dc.language.isoen_US
dc.relationNow published in Nature Communications doi: 10.1038/s41467-021-24965-1
dc.rightsThe copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectMicrobiology
dc.subjectantibiotic resistance
dc.subjectnucleotides
dc.subjectstructure
dc.subjectAmino Acids, Peptides, and Proteins
dc.subjectBacteria
dc.subjectBiochemistry, Biophysics, and Structural Biology
dc.subjectMicrobiology
dc.titleMechanism of LolCDE as a molecular extruder of bacterial triacylated lipoproteins [preprint]
dc.typePreprint
dc.source.journaltitlebioRxiv
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=3044&amp;context=faculty_pubs&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/faculty_pubs/2025
dc.identifier.contextkey23564883
refterms.dateFOA2022-08-23T15:55:43Z
html.description.abstract<p><p id="x-x-x-p-3">Present in all bacteria, lipoproteins are central in bacterial growth and antibiotic resistance. These proteins use lipid acyl chains attached to the N-terminal cysteine residue to anchor on the outer surface of cytoplasmic membrane. In Gram-negative bacteria, many lipoproteins are transported to the outer membrane (OM), a process dependent on the ATP-binding cassette (ABC) transporter LolCDE which extracts the OM-targeted lipoproteins from the cytoplasmic membrane for subsequent trafficking across the periplasm. Lipid-anchored proteins pose a unique challenge for transport machinery as they have both hydrophobic lipid moieties and soluble protein component, and the underlying mechanism is poorly understood. Here we determined the cryo-EM structures of nanodisc-embedded LolCDE in the nucleotide-free and nucleotide-bound states at 3.8-Å and 3.5-Å resolution, respectively. The structural analyses, together with biochemical and mutagenesis studies, uncover how LolCDE specifically recognizes its substrate by establishing multiple interactions with the lipid and N-terminal peptide moieties of the lipoprotein, and identify the amide-linked acyl chain as the key element for LolCDE interaction. Upon nucleotide binding, the transmembrane helices and the periplasmic domains of LolCDE undergo large-scale, asymmetric movements, resulting in extrusion of the captured lipoprotein. Comparison of LolCDE and MacB reveals the conserved mechanism of type VII ABC transporters and emphasizes the unique properties of LolCDE as a molecule extruder of triacylated lipoproteins.</p>
dc.identifier.submissionpathfaculty_pubs/2025
dc.contributor.departmentDepartment of Biochemistry and Molecular Pharmacology


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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
Except where otherwise noted, this item's license is described as The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.