title: Chimeras of Candida albicans Cdr1p and Cdr2p reveal features of pleiotropic drug resistance transporter structure and function.
abstract: Members of the pleiotropic drug resistance (PDR) family of ATP binding cassette (ABC) transporters consist of two homologous halves, each containing a nucleotide binding domain (NBD) and a transmembrane domain (TMD). The PDR transporters efflux a variety of hydrophobic xenobiotics and despite the frequent association of their overexpression with the multidrug resistance of fungal pathogens, the transport mechanism of these transporters is poorly understood. Twenty-eight chimeric constructs between Candida albicans Cdr1p (CaCdr1p) and Cdr2p (CaCdr2p), two closely related but functionally distinguishable PDR transporters, were expressed in Saccharomyces cerevisiae. All chimeras expressed equally well, localized properly at the plasma membrane, retained their transport ability, but their substrate and inhibitor specificities differed significantly between individual constructs. A detailed characterization of these proteins revealed structural features that contribute to their substrate specificities and their transport mechanism. It appears that most transmembrane spans of CaCdr1p and CaCdr2p provide or affect multiple, probably overlapping, substrate and inhibitor binding site(s) similar to mammalian ABC transporters. The NBDs, in particular NBD1 and/or the ∼150 amino acids N-terminal to NBD1, can also modulate the substrate specificities of CaCdr1p and CaCdr2p.
authors: Department of Bioactive Molecules, National Institute of Infectious Diseases, Tokyo 162-8640, Japan.
authors: Koichi
authors: K
authors: Tanabe
authors: Erwin
authors: E
authors: Lamping
authors: Minoru
authors: M
authors: Nagi
authors: Atsushi
authors: A
authors: Okawada
authors: Ann R
authors: AR
authors: Holmes
authors: Yoshitsugu
authors: Y
authors: Miyazaki
authors: Richard D
authors: RD
authors: Cannon
authors: Brian C
authors: BC
authors: Monk
authors: Masakazu
authors: M
authors: Niimi
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000935:Antifungal Agents / Q000378:metabolism / Q000494:pharmacology; D001692:Biological Transport; D002176:Candida albicans / Q000737:chemistry / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D025141:Drug Resistance, Fungal; D005656:Fungal Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics / Q000378:metabolism
chemical_list: D018528:ATP-Binding Cassette Transporters; D000935:Antifungal Agents; D005656:Fungal Proteins; D011993:Recombinant Fusion Proteins