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Site-specific 5-hydroxytryptophan incorporation into apolipoprotein A-I impairs cholesterol efflux activity and high-density lipoprotein biogenesis

The Journal of biological chemistry, 2020-04, Vol.295 (15), p.4836-4848 [Peer Reviewed Journal]

2020 ;ISSN: 0021-9258 ;EISSN: 1083-351X ;DOI: 10.1074/jbc.RA119.012092 ;PMID: 32098873

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Title:
Site-specific 5-hydroxytryptophan incorporation into apolipoprotein A-I impairs cholesterol efflux activity and high-density lipoprotein biogenesis
Author: Zamanian-Daryoush, Maryam ; Gogonea, Valentin ; DiDonato, Anthony J. ; Buffa, Jennifer A. ; Choucair, Ibrahim ; Levison, Bruce S. ; Hughes, Randall A. ; Ellington, Andrew D. ; Huang, Ying ; Li, Xinmin S. ; DiDonato, Joseph A. ; Hazen, Stanley L.
Subjects: 5-Hydroxytryptophan - genetics ; 5-Hydroxytryptophan - metabolism ; Animals ; apolipoprotein ; Apolipoprotein A-I - genetics ; Apolipoprotein A-I - metabolism ; apolipoprotein A-I dysfunction ; Aryldialkylphosphatase - genetics ; Aryldialkylphosphatase - metabolism ; atherosclerosis ; ATP Binding Cassette Transporter 1 - genetics ; ATP Binding Cassette Transporter 1 - metabolism ; Biological Transport ; cardiovascular disease ; cholesterol ; Cholesterol - metabolism ; coronary artery disease ; genetic code expansion ; high-density lipoprotein (HDL) ; Humans ; Lipoproteins, HDL - biosynthesis ; Mice ; Mice, Knockout ; Molecular Bases of Disease ; non-canonical amino acids ; orthogonal translation ; Oxidation-Reduction ; posttranslational modification ; Protein Binding ; recombinant protein expression ; synthetic biology ; tryptophan ; Tyrosine - metabolism
Is Part Of: The Journal of biological chemistry, 2020-04, Vol.295 (15), p.4836-4848
Description: Apolipoprotein A-I (apoA-I) is the major protein constituent of high-density lipoprotein (HDL) and a target of myeloperoxidase-dependent oxidation in the artery wall. In atherosclerotic lesions, apoA-I exhibits marked oxidative modifications at multiple sites, including Trp72. Site-specific mutagenesis studies have suggested, but have not conclusively shown, that oxidative modification of Trp72 of apoA-I impairs many atheroprotective properties of this lipoprotein. Herein, we used genetic code expansion technology with an engineered Saccharomyces cerevisiae tryptophanyl tRNA-synthetase (Trp-RS):suppressor tRNA pair to insert the noncanonical amino acid 5-hydroxytryptophan (5-OHTrp) at position 72 in recombinant human apoA-I and confirmed site-specific incorporation utilizing MS. In functional characterization studies, 5-OHTrp72 apoA-I (compared with WT apoA-I) exhibited reduced ABC subfamily A member 1 (ABCA1)-dependent cholesterol acceptor activity in vitro (41.73 ± 6.57% inhibition; p < 0.01). Additionally, 5-OHTrp72 apoA-I displayed increased activation and stabilization of paraoxonase 1 (PON1) activity (μmol/min/mg) when compared with WT apoA-I and comparable PON1 activation/stabilization compared with reconstituted HDL (WT apoA-I, 1.92 ± 0.04; 5-OHTrp72 apoA-I, 2.35 ± 0.0; and HDL, 2.33 ± 0.1; p < 0.001, p < 0.001, and p < 0.001, respectively). Following injection into apoA-I–deficient mice, 5-OHTrp72 apoA-I reached plasma levels comparable with those of native apoA-I yet exhibited significantly reduced (48%; p < 0.01) lipidation and evidence of HDL biogenesis. Collectively, these findings unequivocally reveal that site-specific oxidative modification of apoA-I via 5-OHTrp at Trp72 impairs cholesterol efflux and the rate-limiting step of HDL biogenesis both in vitro and in vivo.
Publisher: United States: Elsevier Inc
Language: English
Identifier: ISSN: 0021-9258
EISSN: 1083-351X
DOI: 10.1074/jbc.RA119.012092
PMID: 32098873
Source: MEDLINE
PubMed Central
Alma/SFX Local Collection

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Site-specific 5-hydroxytryptophan incorporation into apolipoprotein A-I impairs cholesterol efflux activity and high-density lipoprotein biogenesis

2020 ;ISSN: 0021-9258 ;EISSN: 1083-351X ;DOI: 10.1074/jbc.RA119.012092 ;PMID: 32098873

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