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Tytuł:
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Translocation of Non-Canonical Polypeptides into Cells Using Protective Antigen.
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Autorzy:
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Rabideau AE; Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue 18-596, Cambridge, MA 02139.
Liao X; Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue 18-596, Cambridge, MA 02139.
Akçay G; Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue 18-596, Cambridge, MA 02139.
Pentelute BL; Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue 18-596, Cambridge, MA 02139.
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Źródło:
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Scientific reports [Sci Rep] 2015 Jul 16; Vol. 5, pp. 11944. Date of Electronic Publication: 2015 Jul 16.
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Typ publikacji:
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Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.
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Język:
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English
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Imprint Name(s):
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Original Publication: London : Nature Publishing Group, copyright 2011-
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MeSH Terms:
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Antigens, Bacterial/*metabolism
Bacterial Toxins/*metabolism
Peptides/*metabolism
Amino Acid Sequence ; Cytosol/metabolism ; Peptides/chemistry ; Protein Transport
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References:
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Grant Information:
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U54 AI057159 United States AI NIAID NIH HHS
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Substance Nomenclature:
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0 (Antigens, Bacterial)
0 (Bacterial Toxins)
0 (Peptides)
0 (anthrax toxin)
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Entry Date(s):
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Date Created: 20150717 Date Completed: 20160808 Latest Revision: 20190108
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Update Code:
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20240104
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PubMed Central ID:
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PMC4503955
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DOI:
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10.1038/srep11944
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PMID:
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26178180
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A variety of pathogenic bacteria infect host eukaryotic cells using protein toxins, which enter the cytosol and exert their cytotoxic effects. Anthrax lethal toxin, for example, utilizes the membrane-spanning translocase, protective antigen (PA) pore, to deliver the protein toxin lethal factor (LF) from the endosome into the cytosol of cells. Previous work has investigated the delivery of natural peptides and enzymatic domains appended to the C-terminus of the PA-binding domain of lethal factor (LFN) into the cytosol via PA pore. Here, we move beyond natural amino acids and systematically investigate the translocation of polypeptide cargo containing non-canonical amino acids and functionalities through PA pore. Our results indicate translocation is not perturbed with alterations to the peptide backbone or side-chain. Moreover, despite their structural complexity, we found that the small molecule drugs, doxorubicin and monomethyl auristatin F (MMAF) translocated efficiently through PA pore. However, we found cyclic peptides and the small molecule drug docetaxel abrogated translocation due to their large size and structural rigidity. For cargos that reached the cytosol, we demonstrated that each remained intact after translocation. These studies show PA is capable of translocating non-canonical cargo provided it is in a conformational state conducive for passage through the narrow pore.