ABCMdb

ABCA1 p.Cys1111Ser

Predicted by SNAP2:	A: N (66%), D: D (91%), E: D (85%), F: D (75%), G: D (80%), H: D (85%), I: D (80%), K: D (91%), L: D (80%), M: D (71%), N: D (80%), P: D (91%), Q: D (85%), R: D (91%), S: D (75%), T: D (71%), V: D (71%), W: D (91%), Y: D (85%),
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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[hide] Adenosine-triphosphate-binding cassette transporte... Trends Cardiovasc Med. 2010 Feb;20(2):41-9. Kang MH, Singaraja R, Hayden MR
Adenosine-triphosphate-binding cassette transporter-1 trafficking and function.
Trends Cardiovasc Med. 2010 Feb;20(2):41-9., [PMID:20656214]

Abstract [show]
Mutations in the adenosine-triphosphate-binding cassette transporter-1 (ABCA1) lead to Tangier disease, a genetic disorder characterized by an almost complete absence of plasma high-density lipoprotein cholesterol. Although the importance of ABCA1 localization to its cholesterol efflux function has been extensively characterized, the cellular itinerary of ABCA1 leading to the plasma membrane is not fully elucidated. This review will summarize the current knowledge of ABCA1 trafficking and its relationship to function. Understanding these crucial processes provides potential novel therapeutic targets to regulate high-density lipoprotein biogenesis through influencing pathways of ABCA1 trafficking.

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No. Sentence Comment
133 Inhibiting this modification either pharmacologically or by mutating the sites of palmitoylation (C3S/C23S/C1110S/C1111S) (Figure 2) dramatically reduces ABCA1 at the cell surface and decreases cholesterol and phospholipid efflux to apoA-I. Login to comment
134 Inhibiting this modification either pharmacologically or by mutating the sites of palmitoylation (C3S/C23S/C1110S/C1111S) (Figure 2) dramatically reduces ABCA1 at the cell surface and decreases cholesterol and phospholipid efflux to apoA-I. Login to comment

[hide] Palmitoylation of ATP-binding cassette transporter... Circ Res. 2009 Jul 17;105(2):138-47. Epub 2009 Jun 25. Singaraja RR, Kang MH, Vaid K, Sanders SS, Vilas GL, Arstikaitis P, Coutinho J, Drisdel RC, El-Husseini Ael D, Green WN, Berthiaume L, Hayden MR
Palmitoylation of ATP-binding cassette transporter A1 is essential for its trafficking and function.
Circ Res. 2009 Jul 17;105(2):138-47. Epub 2009 Jun 25., [PMID:19556522]

Abstract [show]
ATP-binding cassette transporter (ABC)A1 lipidates apolipoprotein A-I both directly at the plasma membrane and also uses lipids from the late endosomal or lysosomal compartment in the internal lipidation of apolipoprotein A-I. However, how ABCA1 targeting to these specific membranes is regulated remains unknown. Palmitoylation is a dynamically regulated lipid modification that targets many proteins to specific membrane domains. We hypothesized that palmitoylation may also regulate ABCA1 transport and function. Indeed, ABCA1 is robustly palmitoylated at cysteines 3, -23, -1110, and -1111. Abrogation of palmitoylation of ABCA1 by mutation of the cysteines results in a reduction of ABCA1 localization at the plasma membranes and a reduction in the ability of ABCA1 to efflux lipids to apolipoprotein A-I. ABCA1 is palmitoylated by the palmitoyl transferase DHHC8, and increasing DHHC8 protein results in increased ABCA1-mediated lipid efflux. Thus, palmitoylation regulates ABCA1 localization at the plasma membrane, and regulates its lipid efflux ability.

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108 Assessment of palmitoylation of these sites in the context of full-length ABCA1 showed that ABCA1 was still palmitoylated (Figure 3D, lane C1110/C1111S). Login to comment
109 However, generation of the quadruple mutant C3/23/1110/1111S in full-length ABCA1 resulted in a significant reduction in ABCA1 palmitoylation (Figure 3D, lane C3/C23/C1110/C1111S; and Figure 3E). Login to comment
129 We generated stable cell lines harboring each of the C3S, C23S, C1110S, and C1111S mutants singly and in combination and determined the extent of both cholesterol and phospholipid efflux to ApoA-I facilitated by these cell lines. Login to comment
136 C3S/C23S .....S.…………….……….…….…......S…………………..………..…..………………… C1110S/C1111S ....……………………………………………………..………………..…..….SS……….……. Login to comment
137 C3S/C23S/ C1110S/C1111S .....S.………………………......…......S……………..…..…..….....SS…..…………. Login to comment
138 B C3/C23/C1110/C1111S C3/C23SC 100KDa W T C3S C23S IP: α-His WB: α-Myc 75KDa 100KDa 75KDa 3H fluorogram W T C3S C23S C3/C23S C1110/C1111S WB: α-ABCA1 3H fluorogram 250KDa 250KDa D COOHH2N B A B A C C C3S C23S C1110S C1111S WT C3/C23/C1110/C1111S Palmitoylation (Normalizedtototalprotein) E 0 20 40 60 80 100 120 p=0.000002 W T C3/23/1110/1111SW T C3/23/1110/1111SW T C3/23/1110/1111S 3H fluorogram ABCA1 ABCA1 250KDa 250KDa WB: α-ABCA1 Figure 3. Login to comment
169 A D p=0.0007 p=0.04 p=0.002 p=0.0005 p=0.0002 p<0.0001 0 20 40 60 80 100 120 W T C 3S C 23SC 3S/C 23S C 1110S/C 1111S C 3/C 23/C 1110/C 1111S M 1091T %cholesterolefflux(normalizedtowt) p=0.003 p=0.009p=0.01 p=0.03 p=0.03 p<0.0001 0 20 40 60 80 100 120 W T C 3S C 23SC 3S/C 23S C 1110S/C 1111S C 3/C 23/C 1110/C 1111S M 1091T %phosphocholineefflux(normalizedtowt) Empty Vector WT- No Biotin 150 100 250 75 50 37 Input IP Input IP Input IP WT+Biotin C3/C23/ C1110/C111S+Biotin ABCA1 GAPDH Controls WB: αABCA1 WB: αGAPDH C3/C23/C1110/C1111S 0 20 40 60 80 100 120 p=0.00003 W T BiotinlabeledABCA1(normalizedtoWT) Input IP B C Figure 5. Login to comment
103 Assessment of palmitoylation of these sites in the context of full-length ABCA1 showed that ABCA1 was still palmitoylated (Figure 3D, lane C1110/C1111S). Login to comment
104 However, generation of the quadruple mutant C3/23/1110/1111S in full-length ABCA1 resulted in a significant reduction in ABCA1 palmitoylation (Figure 3D, lane C3/C23/C1110/C1111S; and Figure 3E). Login to comment
124 We generated stable cell lines harboring each of the C3S, C23S, C1110S, and C1111S mutants singly and in combination and determined the extent of both cholesterol and phospholipid efflux to ApoA-I facilitated by these cell lines. Login to comment
131 C3S/C23S .....S.ߪߪߪߪߪ.ߪߪߪ.ߪߪ.ߪ......Sߪߪߪߪߪߪߪ..ߪߪߪ..ߪ..ߪߪߪߪߪߪߪ C1110S/C1111S ....ߪߪߪߪߪߪߪߪߪߪߪߪߪߪߪߪߪߪߪߪ..ߪߪߪߪߪߪ..ߪ..ߪ.SSߪߪߪ.ߪߪ. Login to comment
132 C3S/C23S/ C1110S/C1111S .....S.ߪߪߪߪߪߪߪߪߪ......ߪ......Sߪߪߪߪߪ..ߪ..ߪ..ߪ.....SSߪ..ߪߪߪߪ. Login to comment
133 B C 3 / C 2 3 / C 1 1 1 0 / C 1 1 1 1 S C3/C23S C 100KDa W T C3S C23S IP: b1;-His WB: b1;-Myc 75KDa 100KDa 75KDa 3H fluorogram W T C 3 S C 2 3 S C 3 / C 2 3 S C 1 1 1 0 / C 1 1 1 1 S WB: b1;-ABCA1 3H fluorogram 250KDa 250KDa D COOH H2N B A B A C C C3S C23S C1110S C1111S WT C3/C23/C1110/C1111S Palmitoylation (Normalized to total protein) E 0 20 40 60 80 100 120 p=0.000002 W T C 3 / 2 3 / 1 1 1 0 / 1 1 1 1 S W T C 3 / 2 3 / 1 1 1 0 / 1 1 1 1 S W T C 3 / 2 3 / 1 1 1 0 / 1 1 1 1 S 3H fluorogram ABCA1 ABCA1 250KDa 250KDa WB: b1;-ABCA1 Figure 3. Login to comment
164 A D p=0.0007 p=0.04 p=0.002 p=0.0005 p=0.0002 p<0.0001 0 20 40 60 80 100 120 W T C 3 S C 2 3 S C 3 S / C 2 3 S C 1 1 1 0 S / C 1 1 1 1 S C 3 / C 2 3 / C 1 1 1 0 / C 1 1 1 1 S M 1 0 9 1 T % cholesterol efflux (normalized to wt) p=0.003 p=0.009p=0.01 p=0.03 p=0.03 p<0.0001 0 20 40 60 80 100 120 W T C 3 S C 2 3 S C 3 S / C 2 3 S C 1 1 1 0 S / C 1 1 1 1 S C 3 / C 2 3 / C 1 1 1 0 / C 1 1 1 1 S M 1 0 9 1 T %phosphocholine efflux (normalized to wt) Empty Vector WT- No Biotin 150 100 250 75 50 37 Input IP Input IP Input IP WT+Biotin C3/C23/ C1110/C111S+Biotin ABCA1 GAPDH Controls WB: b1;ABCA1 WB: b1;GAPDH C3/C23/C1110/C1111S 0 20 40 60 80 100 120 p=0.00003 W T Biotin labeled ABCA1 (normalized to WT) Input IP B C Figure 5. Login to comment