Proximal Cysteines that Enhance Lysine N-Acetylation of Cytosolic Proteins in Mice Are Less Conserved in Longer-Living Species

• Published in: Cell reports (Cambridge) Vol. 24; no. 6; pp. 1445 - 1455
• Main Authors: James, Andrew M., Smith, Anthony C., Smith, Cassandra L., Robinson, Alan J., Murphy, Michael P.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07.08.2018; Cell Press; Elsevier
• Subjects: Acetylation; Animals; Cysteine - metabolism; Cytosol - metabolism; Lysine - metabolism; Mice
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2018.07.007

Acetyl-coenzyme A (CoA) is an abundant metabolite that can also alter protein function through non-enzymatic N-acetylation of protein lysines. This N-acetylation is greatly enhanced in vitro if an adjacent cysteine undergoes initial S-acetylation, as this can lead to S→N transfer of the acetyl moiety. Here, using modeled mouse structures of 619 proteins N-acetylated in mouse liver, we show lysine N-acetylation is greater in vivo if a cysteine is within ∼10 Å. Extension to the genomes of 52 other mammalian and bird species shows pairs of proximal cysteine and N-acetylated lysines are less conserved, implying most N-acetylation is detrimental. Supporting this, there is less conservation of cytosolic pairs of proximal cysteine and N-acetylated lysines in species with longer lifespans. As acetyl-CoA levels are linked to nutrient supply, these findings suggest how dietary restriction could extend lifespan and how pathologies resulting from dietary excess may occur. [Display omitted] •Creation of a mouse structural library of in vivo lysine N-acetylation on 619 proteins•Proximal cysteines enhance protein lysine N-acetylation in vivo•Proximal N-acetylated lysine and cysteine residues are less conserved•Conservation of these proximal residues is lower in species with longer lifespans Acetyl-CoA non-enzymatically N-acetylates protein lysines. Using proteins N-acetylated in mouse liver, James et al. show N-acetylation is greater if a cysteine is within ∼10 Å. These pairs of proximal cysteine and N-acetylated lysines are less conserved in species with longer lifespans. This might explain how dietary restriction extends lifespan.