ABCMdb

ABCB1 p.Trp708Arg

Predicted by SNAP2:	A: D (59%), C: N (57%), D: D (80%), E: D (75%), F: D (59%), G: D (71%), H: D (75%), I: D (53%), K: D (71%), L: N (61%), M: N (53%), N: D (75%), P: D (80%), Q: D (75%), R: D (66%), S: D (71%), T: N (57%), V: D (59%), Y: N (53%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: D, T: D, V: D, Y: D,

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Publications
[hide] The W232R suppressor mutation promotes maturation ... Biochemistry. 2011 Feb 8;50(5):672-85. Epub 2011 Jan 11. Loo TW, Bartlett MC, Clarke DM
The W232R suppressor mutation promotes maturation of a truncation mutant lacking both nucleotide-binding domains and restores interdomain assembly and activity of P-glycoprotein processing mutants.
Biochemistry. 2011 Feb 8;50(5):672-85. Epub 2011 Jan 11., 2011-02-08 [PMID:21182301]

Abstract [show]
ATP-binding cassette (ABC) proteins contain two nucleotide-binding domains (NBDs) and two transmembrane (TM) domains (TMDs). Interdomain interactions and packing of the TM segments are critical for function, and disruption by genetic mutations contributes to disease. P-glycoprotein (P-gp) is a useful model to identify mechanisms that repair processing defects because numerous arginine suppressor mutations have been identified in the TM segments. Here, we tested the prediction that a mechanism of arginine rescue was to promote intradomain interactions between TM segments and restore interdomain assembly. We found that suppressor W232R(TM4/TMD1) rescued mutants with processing mutations in any domain and restored defective NBD1-NBD2, NBD1-TMD2, and TMD1-TMD2 interactions. W232R also promoted packing of the TM segments because it rescued a truncation mutant lacking both NBDs. The mechanism of W232R rescue likely involved intradomain hydrogen bond interactions with Asn296(TM5) since only N296A abolished rescue by W232R and rescue was only observed when Trp232 was replaced with hydrogen-bonding residues. In TMD2, suppressor T945R(TM11) also promoted packing of the TM segments because it rescued the truncation mutant lacking the NBDs and suppressed formation of alternative topologies. We propose that T945R rescue was mediated by interactions with Glu875(TM10) since T945E/E875R promoted maturation while T945R/E875A did not.

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Sentences [show]
No. Sentence Comment
147 The effect of the W136R, W212R, W315R, W708R, and W855R mutations on maturation of wild-type P-gp was then tested. Login to comment
149 All of the mutants except W708R (Figure 2D, lane 9) expressed the mature 170 kDa protein as the major product (Figure 2D, lanes 1, 3, 5, 7, and 11), and the amount of mature protein increased in the presence of cyclosporin A (Figure 2D, lanes 2, 4, 6, 8, and 12). Login to comment
150 The major product in mutant W708R was the immature 150 kDa protein (Figure 2D, lane 9). Login to comment