Journal
JOURNAL OF PROTEOME RESEARCH
Volume 17, Issue 6, Pages 2156-2164Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jproteome.8b00100
Keywords
HDL efflux; cholesterol; atherosclerosis; apolipoproteins; proteoforms; top-down proteomics; palmitoylation; ApoA-I; acylations
Categories
Funding
- American Heart Association [SDG 27250022]
- National Institute of Health [K23 HL133601-01, RO1 HL081141]
- National Institute of General Medical Sciences [P41 GM108569]
Ask authors/readers for more resources
Top-down proteomics (TDP) allows precise determination/characterization of the different proteoforms derived from the expression of a single gene. In this study, we targeted apolipoprotein A-I (ApoA-I), a mediator of high density-lipoprotein cholesterol efflux (HDL-E), which is inversely associated with coronary heart disease risk. Absolute ApoA-I concentration and allelic variation only partially explain interindividual HDL-E variation. Therefore, we hypothesize that differences in HDL-E are associated with the abundances of different ApoA-I proteoforms. Here, we present a targeted TDP methodology to characterize ApoA-I proteoforms in serum samples and compare their abundances between individuals. We characterized 18 ApoA-I proteoforms using selected-ion monitoring coupled to electron-transfer dissociation mass spectrometry. We then compared the abundances of these proteoforms between two groups of four participants, representing the individuals with highest and lowest HDL-E values within the Chicago Healthy Aging Study (n = 420). Six proteoforms showed significantly (p < 0.0005) higher intensity in high HDL-E individuals: canonical ApoA-I [fold difference (fd) = 1.17], carboxymethylated ApoA-I (fd = 1.24) and, with highest difference, four fatty acylated forms: palmitoylated (fd = 2.16), oleoylated (fd = 2.08), arachidonoylated (fd = 2.31) and one bearing two modifications: palmitoylation and truncation (fd = 2.13). These results demonstrate translational potential for targeted TDP in revealing, with high sensitivity, associations between interindividual proteoform variation and physiological differences underlying disease risk.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available