Ratjadone and leptomycin B block CRM1-dependent nuclear export by identical mechanisms.
Research on the export of proteins and nucleic acids from the nucleus to the cytoplasm has greatly gained from the discovery that the actinobacterial toxin leptomycin B (LMB) specifically inactivates the export receptor chromosomal region maintenance 1 (CRM1). Recently, it was shown that myxobacterial cytotoxins, named ratjadones (RATs), also bind to CRM1 and inhibit nuclear export. However, the reaction mechanism of RATs was not resolved. Here, we show that LMB and RAT A employ the same molecular mechanism to inactivate CRM1. Alkylation of residue Cys528 of CRM1 determines both LMB and RAT sensitivity and prevents nuclear export of CRM1 cargo proteins.
Abteilung Zelluläre Signalverarbeitung, Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Freie Universität Berlin, Robert-Rössle-Str. 10, 13125 Berlin, Germany.
Torsten
T
Meissner
Eberhard
E
Krause
Uwe
U
Vinkemeier
D021581:Active Transport, Cell Nucleus / Q000187:drug effects* / Q000502:physiology; D000478:Alkylation; D019943:Amino Acid Substitution; D000935:Antifungal Agents / Q000494:pharmacology*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D003545:Cysteine / Q000737:chemistry; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology*; D005982:Glutathione Transferase / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D028884:Karyopherins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D008845:Microinjections; D011753:Pyrones / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D000097606:Exportin 1 Protein
D000935:Antifungal Agents; D003545:Cysteine; D005231:Fatty Acids, Unsaturated; D005982:Glutathione Transferase; D028884:Karyopherins; D011753:Pyrones; D018160:Receptors, Cytoplasmic and Nuclear; D011993:Recombinant Fusion Proteins; D012694:Serine; D000097606:Exportin 1 Protein; C429103:ratjadone; C038753:leptomycin B