ABCA1 p.Tyr115Cys
| Predicted by SNAP2: | A: D (63%), C: D (63%), D: D (71%), E: D (71%), F: N (57%), G: D (66%), H: N (66%), I: N (53%), K: D (71%), L: N (53%), M: D (63%), N: D (59%), P: D (80%), Q: D (63%), R: D (59%), S: D (63%), T: D (59%), V: D (59%), W: D (63%), |
| Predicted by PROVEAN: | A: N, C: N, D: N, E: N, F: N, G: N, H: N, I: N, K: N, L: N, M: N, N: N, P: N, Q: N, R: N, S: N, T: N, V: N, W: N, |
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[hide] Tyrosine 192 in apolipoprotein A-I is the major si... J Biol Chem. 2005 Feb 18;280(7):5983-93. Epub 2004 Nov 30. Shao B, Bergt C, Fu X, Green P, Voss JC, Oda MN, Oram JF, Heinecke JW
Tyrosine 192 in apolipoprotein A-I is the major site of nitration and chlorination by myeloperoxidase, but only chlorination markedly impairs ABCA1-dependent cholesterol transport.
J Biol Chem. 2005 Feb 18;280(7):5983-93. Epub 2004 Nov 30., [PMID:15574409]
Abstract [show]
High density lipoprotein (HDL) isolated from human atherosclerotic lesions and the blood of patients with established coronary artery disease contains elevated levels of 3-nitrotyrosine and 3-chlorotyrosine. Myeloperoxidase (MPO) is the only known source of 3-chlorotyrosine in humans, indicating that MPO oxidizes HDL in vivo. In the current studies, we used tandem mass spectrometry to identify the major sites of tyrosine oxidation when lipid-free apolipoprotein A-I (apoA-I), the major protein of HDL, was exposed to MPO or peroxynitrite (ONOO(-)). Tyrosine 192 was the predominant site of both nitration and chlorination by MPO and was also the major site of nitration by ONOO(-). Electron paramagnetic spin resonance studies of spin-labeled apoA-I revealed that residue 192 was located in an unusually hydrophilic environment. Moreover, the environment of residue 192 became much more hydrophobic when apoA-I was incorporated into discoidal HDL, and Tyr(192) of HDL-associated apoA-I was a poor substrate for nitration by both myeloperoxidase and ONOO(-), suggesting that solvent accessibility accounted in part for the reactivity of Tyr(192). The ability of lipid-free apoA-I to facilitate ATP-binding cassette transporter A1 cholesterol transport was greatly reduced after chlorination by MPO. Loss of activity occurred in concert with chlorination of Tyr(192). Both ONOO(-) and MPO nitrated Tyr(192) in high yield, but unlike chlorination, nitration minimally affected the ability of apoA-I to promote cholesterol efflux from cells. Our results indicate that Tyr(192) is the predominant site of nitration and chlorination when MPO or ONOO(-) oxidizes lipid-free apoA-I but that only chlorination markedly reduces the cholesterol efflux activity of apoA-I. This impaired biological activity of chlorinated apoA-I suggests that MPO-mediated oxidation of HDL might contribute to the link between inflammation and cardiovascular disease.
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No. Sentence Comment
160 The apoA-I cysteine substitutions Y18C, Y29C, Y115C, Y166C, Y192C, and Y236C were bacterially expressed, purified, and labeled as described (50).
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ABCA1 p.Tyr115Cys 15574409:160:46
status: NEW159 The apoA-I cysteine substitutions Y18C, Y29C, Y115C, Y166C, Y192C, and Y236C were bacterially expressed, purified, and labeled as described (50).
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ABCA1 p.Tyr115Cys 15574409:159:46
status: NEW