ABCMdb

PMID: 21389634

Ueda K
ABC proteins protect the human body and maintain optimal health.
Biosci Biotechnol Biochem. 2011;75(3):401-9. Epub 2011 Mar 7., [PubMed]

Sentences

No. Mutations Sentence Comment

15 ABCB1 p.Gly185Val Human MDR1 cDNA, now also called ABCB1 by the HUGO (Human Gene Organization) Nomenclature Committee, was isolated from a multidrug-resistant KB carcinoma cell line, KB-C2.5, selected for its resistance to colchicines, in 1986,1,2) and was found to code for P-glycoprotein,3) a surface glycoprotein reported to be overexpressed in drug-resistant Chinese hamster ovary cell mutants.4) Overexpression of human and mouse MDR1 conferred resistance to many drugs, including Vinca alkaloids, anthracyclines, epipodophyllotoxins, and taxol.5-7) A few years later, Kioka isolated human MDR1 cDNA from the adrenal, and found that cDNA isolated from KB-C2.51,2) was associated with a Gly-to-Val substitution at position 185 in the predicted cytoplasmic loop between TM2 and TM3.8) This mutation increased resistance to colchicine and decreased resistance to vinblastine.8,9) MDR1 is a 1,280 amino-acid protein with two symmetrical halves connected by a short linker region.1) Each half consists of six transmembrane -helices (TM) followed by a nucleotide binding domain (NBD),10) in which ATP is hydrolyzed to energize transport (Fig. 1). Login to comment 96 ABCA1 p.Trp590Ser ABCA1 p.Trp590Ser ABCA1 p.Trp590Ser ABCA1 p.Trp590Ser The Tangier mutation W590S, with one amino acid substitution in the first ECD, impairs HDL formation.64,66) Nagao analyzed the function of this Tangier mutant in detail, and found that it greatly decreases NaTC-dependent cholesterol and PC efflux.87) The kinetics of apoA-I binding to cells expressing ABCA1- W590S were similar to those for cells expressing wild-type ABCA1, consistently with a previous report that the W590S mutation does not impair apoA-I binding,64,65,88,89) but the W590S mutation delayed the dissociation of apoA-I from ABCA1.87) Based on these results, we proposed a four-step model for ABCA1-mediated HDL formation (Fig. 4),90) at the apoA-I binding step, ATP binding and/or hydrolysis causes conformational changes within the ECDs of ABCA1, to which apoA-I directly binds; at the translocation step, lipid translocation by ABCA1, which is apoA-I-independent occurs; at the loading step, lipid loading of apoA-I bound to ABCA1 occurs; and at the dissociation step, dissociation of lipid-loaded apoA-I from ABCA1 occurs. Login to comment 98 ABCA1 p.Trp590Ser ApoA-I undergoes a conformational transition in response to lipids,91) and lipidated apoA-I does not interact with ABCA1.82,92) Because the W590S mutation impairs the translocation step, apoA-I can remain in lipid-free conformation, which has high affinity for ABCA1. Login to comment