ABCA4 p.Arg2107Pro
| ClinVar: |
c.6320G>A
,
p.Arg2107His
?
, Uncertain significance
c.6320G>C , p.Arg2107Pro ? , not provided |
| Predicted by SNAP2: | A: D (66%), C: D (75%), D: D (71%), E: D (71%), F: D (71%), G: D (71%), H: D (91%), I: D (63%), K: N (61%), L: D (66%), M: D (66%), N: D (53%), P: D (95%), Q: D (59%), S: D (80%), T: N (53%), V: D (66%), W: D (80%), Y: D (66%), |
| 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, 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.Arg2107Pro 24097981:65:136
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.Arg2107Pro 24097981:66:136
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.Arg2107Pro 24097981:220:129
status: NEW223 Finally, the null mutant C1502X associated with Stargardt disease was modified to C1502R to reflect the primary sequence change of the corresponding C1477R mutant in ABCA1 linked to Tangier disease.
X
ABCA4 p.Arg2107Pro 24097981:223:129
status: NEW226 The levels of expression of the ABCA1 and ABCA4 mutants were generally lower than the corresponding WT proteins with the ABCA1 mutants S100C and R2081W and the corresponding ABCA4 mutants S100P and R2107P expressing at levels less than 25% of WT and the remaining mutants expressing in the range of 35-90% of the WT proteins.
X
ABCA4 p.Arg2107Pro 24097981:226:198
status: NEW229 Variants in the ECD1 (S100C, W590S, and F593L), NBD1 (T929I and N935S), and NBD2 (R2081W) of ABCA1 showed significantly reduced ATPase activities in the range of 20-35% of WT activity (Fig. 7A).
X
ABCA4 p.Arg2107Pro 24097981:229:198
status: NEW239 In contrast, some of the mutants, including ABCA1 mutants T929I and R2081W and related ABCA4 mutants T959I and R2107P, showed partial or complete co-localization with calnexin in a reticular pattern characteristic of the ER.
X
ABCA4 p.Arg2107Pro 24097981:239:111
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.Arg2107Pro 24097981:68:136
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.Arg2107Pro 24097981:237:111
status: NEW242 In contrast, some of the mutants, including ABCA1 mutants T929I and R2081W and related ABCA4 mutants T959I and R2107P, showed partial or complete co-localization with calnexin in a reticular pattern characteristic of the ER.
X
ABCA4 p.Arg2107Pro 24097981:242:111
status: NEW218 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.Arg2107Pro 24097981:218:129
status: NEW224 The levels of expression of the ABCA1 and ABCA4 mutants were generally lower than the corresponding WT proteins with the ABCA1 mutants S100C and R2081W and the corresponding ABCA4 mutants S100P and R2107P expressing at levels less than 25% of WT and the remaining mutants expressing in the range of 35-90% of the WT proteins.
X
ABCA4 p.Arg2107Pro 24097981:224:198
status: NEW