Multidrug resistance mediated by a bacterial homolog of the human multidrug transporter MDR1.
Resistance of Lactococcus lactis to cytotoxic compounds shares features with the multidrug resistance phenotype of mammalian tumor cells. Here, we report the gene cloning and functional characterization in Escherichia coli of LmrA, a lactococcal structural and functional homolog of the human multidrug resistance P-glycoprotein MDR1. LmrA is a 590-aa polypeptide that has a putative topology of six alpha-helical transmembrane segments in the N-terminal hydrophobic domain, followed by a hydrophilic domain containing the ATP-binding site. LmrA is similar to each of the two halves of MDR1 and may function as a homodimer. The sequence conservation between LmrA and MDR1 includes particular regions in the transmembrane domains and connecting loops, which, in MDR1 and the MDR1 homologs in other mammalian species, have been implicated as determinants of drug recognition and binding. LmrA and MDR1 extrude a similar spectrum of amphiphilic cationic compounds, and the activity of both systems is reversed by reserpine and verapamil. As LmrA can be functionally expressed in E. coli, it offers a useful prokaryotic model for future studies on the molecular mechanism of MDR1-like multidrug transporters.
van Veen
H W
HW
Department of Microbiology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Haren, The Netherlands.
Venema
K
K
Bolhuis
H
H
Oussenko
I
I
Kok
J
J
Poolman
B
B
Driessen
A J
AJ
Konings
W N
WN
D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D000595:Amino Acid Sequence; D001426:Bacterial Proteins; D004352:Drug Resistance, Microbial; D018432:Drug Resistance, Multiple; D005798:Genes, Bacterial; D019450:Genes, MDR; D006801:Humans; D007778:Lactobacillus / Q000187:drug effects / Q000235:genetics*; D008565:Membrane Proteins / Q000502:physiology; D008969:Molecular Sequence Data; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
D018528:ATP-Binding Cassette Transporters; D001426:Bacterial Proteins; D008565:Membrane Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C101824:LmrA protein, Lactococcus lactis