ABCMdb

PMID: 20656214

Kang MH, Singaraja R, Hayden MR
Adenosine-triphosphate-binding cassette transporter-1 trafficking and function.
Trends Cardiovasc Med. 2010 Feb;20(2):41-9., [PubMed]

Sentences

No. Mutations Sentence Comment

40 ABCA1 p.Gln597Arg ABCA1 p.Met1091Thr ABCA1 p.Met1091Thr ABCA1 p.Arg587Trp The importance of ABCA1 localization to the PM is observed in several mutations underlying TD (R587W, Q597R, ΔL693, M1091T), where mislocalization of ABCA1 away from the cell surface leads to a significant reduction in cholesterol efflux function (Singaraja et al. 2006). Login to comment 127 ABCA1 p.Gln597Arg ABCA1 p.Arg587Trp ABCA1 p.Asn935His A number of clinically relevant mutations of ABCA1 (R587W, Q597R, ΔL693, N935H) acquire only the core and not the complex oligosaccharide chain and fail to exit the ER (Singaraja et al. 2006). Login to comment 128 ABCA1 p.Gln597Arg ABCA1 p.Arg587Trp ABCA1 p.Asn935His A number of clinically relevant mutations of ABCA1 (R587W, Q597R, ƊL693, N935H) acquire only the core and not the complex oligosaccharide chain and fail to exit the ER (Singaraja et al. 2006). Login to comment 133 ABCA1 p.Cys1111Ser ABCA1 p.Cys23Ser ABCA1 p.Cys1110Ser 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 ABCA1 p.Cys1111Ser ABCA1 p.Cys23Ser ABCA1 p.Cys1110Ser 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 135 ABCA1 p.Cys1477Arg ABCA1 p.Leu1379Phe ABCA1 p.Asp1289Asn Table 2. Summary of ABCA1 domains involved in trafficking and function Domain Amino acids Role Effect on ABCA1 TD mutations in domain Reference NH2 signal anchor sequence 1-60 Proper insertion of ABCA1 into membrane in a type II orientation ABCA1 protein expression, proper glycosylation Fitzgerald et al. 2001 PEST sequence 1283-1306 Target for calpain protease Controls cell-surface concentration of ABCA1 and ABCA1 degradation D1289N, 1284X Wang et al. 2003 "NDF6F1" sequence 1311-1450 ApoA-I binding ApoA-I binding increases ABCA1 stability and cell-surface expression L1379F Mukhamedova et al. 2007 PDZ binding motif 2259-2261 Binding site for PDZ-containing proteins Interactions with PDZ proteins stabilize ABCA1 Munehira et al. 2004, Okuhira et al. 2005 Table 3. Summary of ABCA1 posttranslational modifications involved in trafficking and function Posttranslational modification Amino acids Effect on ABCA1 TD mutations Reference Disulfide bond formation C75, C309, C1463, C1465, C1477 Two disulfide bonds formed between the Nand C-terminal halves of ABCA1 are required for ABCA1 to be fully functional C1477R Hozoji et al. 2009 Glycosylation N98, N400, N489, N1504, N1637 (predicted) Unknown, but glycosylation often plays a role in proper protein folding, stability, and trafficking Bungert et al. 2001 Palmitoylation C3, C23, C1110, C1111 Localization of ABCA1 at the PM Singaraja et al. 2009 Phosphorylation T1286, T1305 Are constitutively phosphorylated; the dephosphorylation of these residues increases ABCA1 stability Martinez et al. 2003 45TCM Vol. 20, No. 2, Once proteins arrive at the trans-Golgi network (TGN), they are sorted for delivery to multiple destinations including the PM, endosomes, or involvement in retrograde transport. Login to comment 136 ABCA1 p.Cys1477Arg ABCA1 p.Leu1379Phe ABCA1 p.Asp1289Asn Table 2. Summary of ABCA1 domains involved in trafficking and function Domain Amino acids Role Effect on ABCA1 TD mutations in domain Reference NH2 signal anchor sequence 1-60 Proper insertion of ABCA1 into membrane in a type II orientation ABCA1 protein expression, proper glycosylation Fitzgerald et al. 2001 PEST sequence 1283-1306 Target for calpain protease Controls cell-surface concentration of ABCA1 and ABCA1 degradation D1289N, 1284X Wang et al. 2003 "NDF6F1" sequence 1311-1450 ApoA-I binding ApoA-I binding increases ABCA1 stability and cell-surface expression L1379F Mukhamedova et al. 2007 PDZ binding motif 2259-2261 Binding site for PDZ-containing proteins Interactions with PDZ proteins stabilize ABCA1 Munehira et al. 2004, Okuhira et al. 2005 Table 3. Summary of ABCA1 posttranslational modifications involved in trafficking and function Posttranslational modification Amino acids Effect on ABCA1 TD mutations Reference Disulfide bond formation C75, C309, C1463, C1465, C1477 Two disulfide bonds formed between the Nand C-terminal halves of ABCA1 are required for ABCA1 to be fully functional C1477R Hozoji et al. 2009 Glycosylation N98, N400, N489, N1504, N1637 (predicted) Unknown, but glycosylation often plays a role in proper protein folding, stability, and trafficking Bungert et al. 2001 Palmitoylation C3, C23, C1110, C1111 Localization of ABCA1 at the PM Singaraja et al. 2009 Phosphorylation T1286, T1305 Are constitutively phosphorylated; the dephosphorylation of these residues increases ABCA1 stability Martinez et al. 2003 Once proteins arrive at the trans-Golgi network (TGN), they are sorted for delivery to multiple destinations including the PM, endosomes, or involvement in retrograde transport. Login to comment