van der Bliek A M, Kooiman P M, Schneider C, Borst P
The Netherlands Cancer Institute, Department of Molecular Biology, Amsterdam.
Gene. 1988 Nov 30;71(2):401-11. 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 Mr 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.
我们利用从肝脏RNA获得的cDNA确定了人类mdr3基因的序列。mdr3基因编码膜蛋白家族（P-糖蛋白）的一个成员，该蛋白在许多多药耐药（MDR）细胞系中过度表达。与其家族成员一样，mdr3编码的蛋白推断分子量为140,000，合成后可能通过糖基化作用而增加。该序列由两个相似的部分组成，每部分都有一系列六个疏水片段，可能形成膜通道。这两部分还具有核苷酸结合共有序列，推测其作为ATP酶并驱动药物转运。推测的ATP酶结构域与人类mdr1基因产物的ATP酶结构域几乎完全相同[Chen等人，《细胞》47(1986)381 - 389]。我们将这种高度的序列保守性归因于重复的基因转换，这从mdr1和mdr3仅在少数沉默突变上存在差异的片段中明显可见。P-糖蛋白家族成员之间的差异在N末端和连接两部分的60个氨基酸的连接区最大。在假定的跨膜结构域中，mdr1和mdr3产物之间约80%的氨基酸是保守的。虽然mdr3的功能尚不清楚，但其与mdr1的高度同源性表明它也编码一种具有广泛特异性的外排泵。
