ABCMdb

ABCA4 p.Cys1502Arg

ClinVar:	c.4506C>T , p.Cys1502= ? , not provided c.4506C>A , p.Cys1502* ? , not provided
Predicted by SNAP2:	A: N (53%), D: D (71%), E: D (59%), F: D (59%), G: D (71%), H: D (53%), I: N (53%), K: D (66%), L: D (53%), M: D (53%), N: D (63%), P: D (66%), Q: D (66%), R: D (66%), S: D (59%), T: D (53%), V: N (61%), W: D (75%), Y: D (66%),
Predicted by PROVEAN:	A: 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, W: D, Y: D,

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Publications
[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. Login to comment
66 Corresponding ABCA4 mutations determined by amino acid alignment with ABCA1 included S100P, W605S, F608L, T959I, N965S, C1502R, T1537M, R2107P, and P2180L. Login to comment
223 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. Login to comment
226 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. Login to comment
232 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. Login to comment
234 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. Login to comment
295 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). Login to comment
68 Corresponding ABCA4 mutations determined by amino acid alignment with ABCA1 included S100P, W605S, F608L, T959I, N965S, C1502R, T1537M, R2107P, and P2180L. Login to comment
237 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. Login to comment
298 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). Login to comment
221 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. Login to comment
293 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). Login to comment