Mistargeted MRPdeltaF728 mutant is rescued by intracellular GSH.
The most common cystic fibrosis-causing mutation is the deletion of the widely conserved phenylalanine 508 (DeltaF508) of CFTR. The mutant is unable to fold correctly and to transit to the plasma membrane. MRP1 belongs to the same subfamily of ABC proteins as CFTR and confers resistance to a wide range of chemotherapeutic drugs. By analogy, phenylalanine 728 was deleted in MRP1. Our results shown that MRPDeltaF728 is correctly targeted to the plasma membrane, actively transports doxorubicin (DOX) and vincristine (VCR) and shares a structure identical to MRP1. Intracellular GSH depletion however results in a mistargeted mutant that is retained into the cytoplasm, while in the same conditions wild-type MRP1 is correctly routed to the plasma membrane. The GSH-protein complex could adopt a stable conformation protected against proteolytic degradation and correctly targeted to the plasma membrane.
Buyse
Frédéric
F
Structure et Fonction des Membranes Biologiques (S.F.M.B.), Centre de Biologie Structurale et de Bioinformatique, Université Libre de Bruxelles, CP 206/2, Bd. du Triomphe, B-1050 Brussels, Belgium.
Vandenbranden
Michel
M
Ruysschaert
Jean-Marie
JM
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D000595:Amino Acid Sequence; D000903:Antibiotics, Antineoplastic / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism; D003903:Deuterium / Q000378:metabolism; D004317:Doxorubicin / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D017354:Point Mutation; D017433:Protein Structure, Secondary; D021381:Protein Transport / Q000502:physiology; D016415:Sequence Alignment
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; C505032:CFTR protein, human; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D004317:Doxorubicin; D003903:Deuterium; D005978:Glutathione