ABCB1 p.Gly722Ala
| Predicted by SNAP2: | A: D (75%), C: D (75%), D: D (85%), E: D (91%), F: D (91%), H: D (85%), I: D (85%), K: D (91%), L: D (91%), M: D (85%), N: D (80%), P: D (91%), Q: D (85%), R: D (91%), S: D (80%), T: D (75%), V: D (85%), W: D (91%), Y: D (91%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: D, F: 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, W: D, Y: D, |
[switch to compact view]
Comments [show]
None has been submitted yet.
[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.
Comments [show]
None has been submitted yet.
No. Sentence Comment
57 The red balls show the locations of Trp232 and the processing mutations at positions 251 (G251V), 490 (ΔY490), 709 (P709A), 722 (G722A), and 1260 (L1260A).
X
ABCB1 p.Gly722Ala 21182301:57:135
status: NEW67 Mutations were introduced into wild-type P-gp or processing mutants containing processing mutations in different domains (G251V in TMD1, ΔY490 in NBD1, P709A in the linker region, G722A in TMD2, or L1260A in NBD2) as described previously (28).
X
ABCB1 p.Gly722Ala 21182301:67:186
status: NEW125 The W232R mutation was introduced into mutants P709A (linker region), G722A (TMD2), or L1260A (NBD2).
X
ABCB1 p.Gly722Ala 21182301:125:70
status: NEW[hide] Thapsigargin or curcumin does not promote maturati... Biochem Biophys Res Commun. 2004 Dec 10;325(2):580-5. Loo TW, Bartlett MC, Clarke DM
Thapsigargin or curcumin does not promote maturation of processing mutants of the ABC transporters, CFTR, and P-glycoprotein.
Biochem Biophys Res Commun. 2004 Dec 10;325(2):580-5., [PMID:15530432]
Abstract [show]
Misprocessed plasma membrane proteins of CFTR and P-glycoprotein (P-gp) are retained in the endoplasmic reticulum (ER) by molecular chaperones. Depletion of the calcium stores in the ER by the SERCA calcium pump inhibitors thapsigargin or curcumin inhibits these interactions and allows the protein to be trafficked to the plasma membrane [Nat. Med. 8 (2002) 485; Science 304 (2004) 600]. We tested this hypothesis by treating various cell lines expressing misprocessed mutants of CFTR or P-gp with thapsigargin or curcumin. Conversion of the immature core-glycosylated protein to mature product was detected by immunoblot analysis of whole cell extracts. Mature product was not detected in any of the misprocessed mutants. By contrast, all misprocessed P-gp mutants were rescued by the chemical chaperone/drug substrate cyclosporin A in a dose-dependent manner. These results show that thapsigargin or curcumin is not effective in rescuing misprocessed mutants of P-gp and CFTR.
Comments [show]
None has been submitted yet.
No. Sentence Comment
59 The processing mutations G300V (TM5) and G722A (TM7) are in TMD1 and TMD2, respectively.
X
ABCB1 p.Gly722Ala 15530432:59:41
status: NEW70 Although the processing mutations (G251V, G300V, DY490, P709A, G722A, F804A, and P1194A) are located in different segments of P-gp, all the mutants could be rescued when expressed with drug substrates such as cyclosporin A.
X
ABCB1 p.Gly722Ala 15530432:70:63
status: NEW90 We then compared the abilities of cyclosporin A, thapsigargin, and curcumin to induce maturation of P-gp processing mutants G251V, G300V, DY490, P709A, G722A, F804A, and P1194A.
X
ABCB1 p.Gly722Ala 15530432:90:152
status: NEW