ABCA4 p.Pro2180Leu
| Predicted by SNAP2: | A: N (66%), C: N (61%), D: N (72%), E: N (66%), F: D (59%), G: N (57%), H: N (66%), I: N (57%), K: N (66%), L: N (53%), M: N (57%), N: N (72%), Q: N (72%), R: N (61%), S: N (72%), T: N (78%), V: N (61%), W: D (71%), 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, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D, |
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[hide] Differential phospholipid substrates and direction... J Biol Chem. 2013 Nov 29;288(48):34414-26. doi: 10.1074/jbc.M113.508812. Epub 2013 Oct 4. Quazi F, Molday RS
Differential phospholipid substrates and directional transport by ATP-binding cassette proteins ABCA1, ABCA7, and ABCA4 and disease-causing mutants.
J Biol Chem. 2013 Nov 29;288(48):34414-26. doi: 10.1074/jbc.M113.508812. Epub 2013 Oct 4., [PMID:24097981]
Abstract [show]
ABCA1, ABCA7, and ABCA4 are members of the ABCA subfamily of ATP-binding cassette transporters that share extensive sequence and structural similarity. Mutations in ABCA1 cause Tangier disease characterized by defective cholesterol homeostasis and high density lipoprotein (HDL) deficiency. Mutations in ABCA4 are responsible for Stargardt disease, a degenerative disorder associated with severe loss in central vision. Although cell-based studies have implicated ABCA proteins in lipid transport, the substrates and direction of transport have not been firmly established. We have purified and reconstituted ABCA1, ABCA7, and ABCA4 into liposomes for fluorescent-lipid transport studies. ABCA1 actively exported or flipped phosphatidylcholine, phosphatidylserine, and sphingomyelin from the cytoplasmic to the exocytoplasmic leaflet of membranes, whereas ABCA7 preferentially exported phosphatidylserine. In contrast, ABCA4 transported phosphatidylethanolamine in the reverse direction. The same phospholipids stimulated the ATPase activity of these ABCA transporters. The transport and ATPase activities of ABCA1 and ABCA4 were reduced by 25% in the presence of 20% cholesterol. Nine ABCA1 Tangier mutants and the corresponding ABCA4 Stargardt mutants showed significantly reduced phospholipid transport activity and subcellular mislocalization. These studies provide the first direct evidence for ABCA1 and ABCA7 functioning as phospholipid transporters and suggest that this activity is an essential step in the loading of apoA-1 with phospholipids for HDL formation.
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No. Sentence Comment
65 Mutations introduced by overlap extension PCR using Pfu AD DNA polymerase in ABCA1 included S100C, W590S, F593L, N935S, T929I, C1477R, T1512M, R2081W, and P2150L.
X
ABCA4 p.Pro2180Leu 24097981:65:148
status: NEW66 Corresponding ABCA4 mutations determined by amino acid alignment with ABCA1 included S100P, W605S, F608L, T959I, N965S, C1502R, T1537M, R2107P, and P2180L.
X
ABCA4 p.Pro2180Leu 24097981:66:148
status: NEW220 Error bars show S.E. Lipid Transport Activity of ABCA Transporters 34420 gardt disease (S100P, F608L, N965S, T959I, T1537M, and R2107P) (Fig. 6A, red).
X
ABCA4 p.Pro2180Leu 24097981:220:83
status: NEW222 These two residues were replaced with serine and leucine, respectively, (W605S and P2180L) corresponding to the disease-causing substitutions in ABCA1.
X
ABCA4 p.Pro2180Leu 24097981:222:83
status: NEW232 ABCA4 variants showed a similar ATPase activity profile as the ABCA1 mutants with the exception of the T1537M mutation of ABCA4, which was significantly lower than the corresponding T1512M mutant in ABCA1.
X
ABCA4 p.Pro2180Leu 24097981:232:254
status: NEW234 As shown in Fig. 8, A and B, the Fl-PC flippase activity of the ABCA1 mutants and the Fl-PE flippase activity of ABCA4 mutants have a similar profile with the ABCA1 variants C1477R, T1512M, and P2150L and corresponding ABCA4 variants C1502R, T1537M, and P2180L showing transport activities ranging from 60 to 80% of the WT protein and the other mutants showing reduced activity in the range of 20-40% of the WT protein.
X
ABCA4 p.Pro2180Leu 24097981:234:254
status: NEW295 The ABCA1/ABCA4 mutants in the ECD1 (S100C/S100P, W590S/ W605S, and F593L/F608L) displayed the lowest activities (20-30% WT), whereas those in the ECD2 (C1477R/C1502R and T1512M/T1537M) and the P2150L/P2180L mutants in the C terminus showed the highest activities (60-100% WT).
X
ABCA4 p.Pro2180Leu 24097981:295:201
status: NEW68 Corresponding ABCA4 mutations determined by amino acid alignment with ABCA1 included S100P, W605S, F608L, T959I, N965S, C1502R, T1537M, R2107P, and P2180L.
X
ABCA4 p.Pro2180Leu 24097981:68:148
status: NEW225 These two residues were replaced with serine and leucine, respectively, (W605S and P2180L) corresponding to the disease-causing substitutions in ABCA1.
X
ABCA4 p.Pro2180Leu 24097981:225:83
status: NEW237 As shown in Fig. 8, A and B, the Fl-PC flippase activity of the ABCA1 mutants and the Fl-PE flippase activity of ABCA4 mutants have a similar profile with the ABCA1 variants C1477R, T1512M, and P2150L and corresponding ABCA4 variants C1502R, T1537M, and P2180L showing transport activities ranging from 60 to 80% of the WT protein and the other mutants showing reduced activity in the range of 20-40% of the WT protein.
X
ABCA4 p.Pro2180Leu 24097981:237:254
status: NEW298 The ABCA1/ABCA4 mutants in the ECD1 (S100C/S100P, W590S/ W605S, and F593L/F608L) displayed the lowest activities (20-30% WT), whereas those in the ECD2 (C1477R/C1502R and T1512M/T1537M) and the P2150L/P2180L mutants in the C terminus showed the highest activities (60-100% WT).
X
ABCA4 p.Pro2180Leu 24097981:298:201
status: NEW293 The ABCA1/ABCA4 mutants in the ECD1 (S100C/S100P, W590S/ W605S, and F593L/F608L) displayed the lowest activities (2030% WT), whereas those in the ECD2 (C1477R/C1502R and T1512M/T1537M) and the P2150L/P2180L mutants in the C terminus showed the highest activities (60-100% WT).
X
ABCA4 p.Pro2180Leu 24097981:293:200
status: NEW