ABCMdb

ABCA4 p.Phe2219Ala

Predicted by SNAP2:	A: D (66%), C: N (57%), D: D (75%), E: D (63%), G: D (80%), H: D (59%), I: N (66%), K: D (63%), L: N (61%), M: N (66%), N: D (66%), P: D (75%), Q: D (53%), R: D (59%), S: D (63%), T: D (59%), V: N (53%), W: N (53%), Y: N (72%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: 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] ATP-binding cassette transporter A1 contains a nov... J Biol Chem. 2004 Nov 12;279(46):48477-85. Epub 2004 Sep 3. Fitzgerald ML, Okuhira K, Short GF 3rd, Manning JJ, Bell SA, Freeman MW
ATP-binding cassette transporter A1 contains a novel C-terminal VFVNFA motif that is required for its cholesterol efflux and ApoA-I binding activities.
J Biol Chem. 2004 Nov 12;279(46):48477-85. Epub 2004 Sep 3., [PMID:15347662]

Abstract [show]
The stimulation of cellular cholesterol and phospholipid efflux by apolipoprotein A-I is mediated by the activity of the ATP-binding cassette transporter A1 (ABCA1). Individuals with Tangier disease harbor loss-of-function mutations in this transporter that have proven useful in illuminating its activity. Here, we analyze a mutation that deletes the last 46 residues of the 2261 amino acid transporter (Delta46) and eliminates its lipid efflux. As the final four amino acids of the C terminus represent a putative PDZ-binding motif, we initially characterized deletion mutants lacking only these residues. Although a moderate decline in lipid efflux was detected, this decline was not as profound as that seen in the Delta46 mutant. Subsequent systematic analysis of the ABCA1 C terminus revealed a novel, highly conserved motif (VFVNFA) that was required for lipid efflux. Alteration of this motif, which is present in some but not all members of the ABCA family, did not prevent trafficking of the transporter to the plasma membrane but did eliminate its binding of apoA-I. Chimeric transporters, generated by substituting the C termini of either ABCA4 or ABCA7 for the endogenous terminus, demonstrated that ABCA1 could stimulate cholesterol efflux without its PDZ-binding motif but not without the VFVNFA motif. When a peptide containing the VFVNFA sequence was introduced into ABCA1-expressing cells, ABCA1-mediated lipid efflux was also markedly inhibited. These results indicate that the C-terminal VFVNFA motif of ABCA1 is essential for its lipid efflux activity. The data also suggest that this motif participates in novel protein-protein interactions that may be shared among members of the ABCA family.

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Sentences [show]
No. Sentence Comment
49 Mutations of the VFVNFA motif of ABCA1 (2215 VFVNFA2220 3 2215 AAAAA- A2220 , 2215 VFVNFA2220 3 2215 VFLYFS2220 , V2215A, F2216A, V2217A, V2217L, N2218A, and F2219A) were generated by overlap PCR. Login to comment
164 To further dissect the motif itself, the contributions of the individual residues within the VFVNFA motif were defined by generating single alanine substitutions (V2215A, F2216A, V2217A, N2218A, and F2219A). Login to comment
165 At moderate expression levels in 293 cells, all of the single mutations showed a near complete loss of efflux activity with the exception of the F2219A mutant, whose activity was similar to that of wild type ABCA1 (Fig. 7A). Login to comment
163 To further dissect the motif itself, the contributions of the individual residues within the VFVNFA motif were defined by generating single alanine substitutions (V2215A, F2216A, V2217A, N2218A, and F2219A). Login to comment