The pattern of apolipoprotein A-I lysine carbamylation reflects its lipidation state and the chemical environment within human atherosclerotic aorta

Protein lysine carbamylation is an irreversible post-translational modification resulting in generation of homocitrulline (N-ε-carbamyllysine), which no longer possesses a charged ε-amino moiety. Two distinct pathways can promote protein carbamylation. One results from urea decomposition, forming an...

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Published in:	The Journal of biological chemistry 2022-04, Vol.298 (4), p.101832-101832, Article 101832
Main Authors:	Battle, Shawna, Gogonea, Valentin, Willard, Belinda, Wang, Zeneng, Fu, Xiaoming, Huang, Ying, Graham, Linda M., Cameron, Scott J., DiDonato, Joseph A., Crabb, John W., Hazen, Stanley L.
Format:	Article
Language:	eng
Subjects:	Aorta - metabolism Aorta - pathology apolipoprotein A-I Apolipoprotein A-I - metabolism Atherosclerosis - metabolism Atherosclerosis - pathology carbamylation cardiovascular disease cyanate high-density lipoprotein homocitrulline Humans Isocyanates Lipoproteins, HDL - metabolism Lysine - metabolism myeloperoxidase oxidation Plaque, Atherosclerotic - pathology Protein Carbamylation Proteomics Urea
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Summary:	Protein lysine carbamylation is an irreversible post-translational modification resulting in generation of homocitrulline (N-ε-carbamyllysine), which no longer possesses a charged ε-amino moiety. Two distinct pathways can promote protein carbamylation. One results from urea decomposition, forming an equilibrium mixture of cyanate (CNO−) and the reactive electrophile isocyanate. The second pathway involves myeloperoxidase (MPO)-catalyzed oxidation of thiocyanate (SCN−), yielding CNO− and isocyanate. Apolipoprotein A-I (apoA-I), the major protein constituent of high-density lipoprotein (HDL), is a known target for MPO-catalyzed modification in vivo, converting the cardioprotective lipoprotein into a proatherogenic and proapoptotic one. We hypothesized that monitoring site-specific carbamylation patterns of apoA-I recovered from human atherosclerotic aorta could provide insights into the chemical environment within the artery wall. To test this, we first mapped carbamyllysine obtained from in vitro carbamylation of apoA-I by both the urea-driven (nonenzymatic) and inflammatory-driven (enzymatic) pathways in lipid-poor and lipidated apoA-I (reconstituted HDL). Our results suggest that lysine residues within proximity of the known MPO-binding sites on HDL are preferentially targeted by the enzymatic (MPO) carbamylation pathway, whereas the nonenzymatic pathway leads to nearly uniform distribution of carbamylated lysine residues along the apoA-I polypeptide chain. Quantitative proteomic analyses of apoA-I from human aortic atheroma identified 16 of the 21 lysine residues as carbamylated and suggested that the majority of apoA-I carbamylation in vivo occurs on “lipid-poor” apoA-I forms via the nonenzymatic CNO− pathway. Monitoring patterns of apoA-I carbamylation recovered from arterial tissues can provide insights into both apoA-I structure and the chemical environment within human atheroma.
ISSN:	0021-9258 1083-351X