ABCB1 p.Ser993Ala
| Predicted by SNAP2: | A: D (59%), C: D (80%), D: D (85%), E: D (85%), F: D (85%), G: D (75%), H: D (80%), I: D (85%), K: D (91%), L: D (91%), M: D (80%), N: D (53%), P: D (91%), Q: D (80%), R: D (85%), T: D (53%), V: D (71%), W: D (91%), Y: D (85%), |
| Predicted by PROVEAN: | A: N, 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, T: N, V: D, W: D, Y: D, |
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[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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No. Sentence Comment
196 (D) HEK 293 cells transfected with A52-tagged mutant G251V/W232R(TM4) containing mutations in potential hydrogen-bonding residues in TM6 (S344A, Q347A, S349A, S351A) or TM12 (Q990A, S992A, S993A) were cultured in the absence (-) or presence (þ) of cyclosporin A (cyclo A).
X
ABCB1 p.Ser993Ala 21182301:196:189
status: NEW241 Maturation was not reduced by the Q990A, S992A, or S993A TM12 mutations (Figure 7C, lanes 7, 8, and 9).
X
ABCB1 p.Ser993Ala 21182301:241:51
status: NEW