PMID: 9169612May 1, 1997Paper

Characterization of the human multidrug resistance protein containing mutations in the ATP-binding cassette signature region

The Biochemical Journal
BakosA Váradi

Abstract

A number of mutants with single amino acid replacements were generated in the highly conserved ATP-binding cassette (ABC)-signature region (amino acids 531-543) of the N-terminal half of the human multidrug resistance (MDR1) protein. The cDNA variants were inserted into recombinant baculoviruses and the MDR1 proteins were expressed in Spodoptera frugiperda (Sf9) insect cells. The level of expression and membrane insertion of the MDR1 variants was examined by immunostaining, and MDR1 function was followed by measuring drug-stimulated ATPase activity. We found that two mutations, L531R and G534V, practically eliminated MDR1 expression; thus these amino acid replacements seem to inhibit the formation of a stable MDR1 protein structure. The MDR1 variants G534D and I541R were expressed at normal levels with normal membrane insertion, but showed a complete loss of drug-stimulated ATPase activity, while mutant R538M yielded full protein expression but with greatly decreased ATPase activity. Increasing the ATP concentration did not restore MDR1 ATPase activity in these variants. Some amino acid replacements in the ABC-signature region (K536I, K536R, I541T and R543S) affected neither the expression and membrane insertion nor the ATPase ...Continue Reading

Citations

Dec 29, 2015·Cellular and Molecular Life Sciences : CMLS·S MacalouA Di Pietro
Dec 15, 2005·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Suresh V AmbudkarZuben E Sauna
Apr 12, 2001·European Journal of Biochemistry·H NagyG Szabó
Jan 31, 2006·FEBS Letters·Annie Frelet, Markus Klein
Apr 9, 2008·Physiological Reviews·Tsung-Yu Chen, Tzyh-Chang Hwang
Mar 28, 2008·The Journal of Pharmacology and Experimental Therapeutics·Nada AblaDeanna L Kroetz
May 25, 2004·Molecular Pharmacology·Xiao-Qin RenShin-ichi Akiyama
Apr 24, 2008·The Journal of Pharmacology and Experimental Therapeutics·Yang LiuJian-Ting Zhang
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