期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 288, 期 42, 页码 30420-30431出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M113.494682
关键词
ABC Transporter; ATPases; Drug Transport; Membrane Proteins; Multidrug Transporters
资金
- National Institutes of Health [GM07721]
- National Science Foundation [MCB1048838]
- Intramural Research Program of the National Institutes of Health, NCI, Center for Cancer Research
- Div Of Molecular and Cellular Bioscience
- Direct For Biological Sciences [1048838] Funding Source: National Science Foundation
Pdr5 is the founding member of a large subfamily of evolutionarily distinct, clinically important fungal ABC transporters containing a characteristic, deviant ATP-binding site with altered Walker A, Walker B, Signature (C-loop), and Q-loop residues. In contrast to these motifs, the D-loops of the two ATP-binding sites have similar sequences, including a completely conserved aspartate residue. Alanine substitution mutants in the deviant Walker A and Signature motifs retain significant, albeit reduced, ATPase activity and drug resistance. The D-loop residue mutants D340A and D1042A showed a striking reduction in plasma membrane transporter levels. The D1042N mutation localized properly had nearly WT ATPase activity but was defective in transport and was profoundly hypersensitive to Pdr5 substrates. Therefore, there was a strong uncoupling of ATPase activity and drug efflux. Taken together, the properties of the mutants suggest an additional, critical intradomain signaling role for deviant ATP-binding sites.
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