Sequence of mdr3 cDNA encoding a human P-glycoprotein

• Published in: Gene Vol. 71; no. 2; pp. 401 - 411
• Main Authors: van der Bliek, A.M., Kooiman, P.M., Schneider, C., Borst, P.
• Format: Journal Article
• Language: English
• Published: Lausanne Elsevier B.V 30.11.1988; Amsterdam Elsevier; New York, NY
• Subjects: Amino Acid Sequence; ATP Binding Cassette Transporter, Subfamily B, Member 1; Bacteriophage lambda - genetics; Base Sequence; Biological and medical sciences; DNA - biosynthesis; DNA - genetics; DNA - isolation & purification; Drug Resistance - genetics; efflux pump; Fundamental and applied biological sciences. Psychology; Genes. Genome; Humans; hydrophobic segment; liver RNA; Membrane Glycoproteins - genetics; membrane transport; Molecular and cellular biology; Molecular genetics; Molecular Sequence Data; multi-drug resistance; Multigene Family; nucleotide-binding domain, rootless tree; Recombinant DNA; Transfection; multi-drug resistance; ORF; nt; efflux pump; Recombinant DNA; bp; kb; cDNA; MDR; nucleotide-binding domain, rootless tree; P-glycoproteins; tms; aa; liver RNA; SSC; ID 50; MoLV; CMV; BAP; PolIk; membrane transport; TAE; hydrophobic segment; nbs; D-MEM; Human; Molecular evolution; Membrane protein; Conserved sequence; Complementary DNA; Nucleotide sequence; Liver; Homology; Hydrophobicity; Phylogeny; Aminoacid sequence
• ISSN: 0378-1119; 1879-0038
• DOI: 10.1016/0378-1119(88)90057-1

We have determined the sequence of the human mdr3 gene using cDNA derived from liver RNA. The mdr3 gene codes for a member of a family of membrane proteins, the P-glycoproteins, overproduced in many multi-drug-resistant (MDR) cell lines. Like its relatives, the protein encoded by mdr3 has a deduced M r of 140 000, which is presumably increased by glycosylation after synthesis. The sequence consists of two similar halves, each with a series of six hydrophobic segments that may form a membrane channel. The halves also possess nucleotide-binding consensus sequences, which presumably act as ATPases and drive drug transport. The presumed ATPase domains are all but identical to those of the human mdr1 gene product [Chen et al., Cell 47 (1986) 381–389]. We attribute this high level of sequence conservation to the repeated gene conversion that is evident from segments in which mdr1 and mdr3 differ only in a few silent mutations. Divergence between P-glycoprotein family members is greatest at the N terminus and in the 60 amino acid linker connecting the two halves. In the putative trans-membrane domains approx. 80% of the amino acids are conserved between the products of mdr1 and mdr3. Although the function of mdr3 is not yet known, its high homology with mdr1 suggests that it also encodes an efflux pump with broad specificity.