Protein lysine crotonylation: past, present, perspective

Abstract

Lysine crotonylation has been discovered in histone and non-histone proteins and found to be involved in diverse diseases and biological processes, such as neuropsychiatric disease, carcinogenesis, spermatogenesis, tissue injury, and inflammation. The unique carbon-carbon π-bond structure indicates that lysine crotonylation may use distinct regulatory mechanisms from the widely studied other types of lysine acylation. In this review, we discussed the regulation of lysine crotonylation by enzymatic and non-enzymatic mechanisms, the recognition of substrate proteins, the physiological functions of lysine crotonylation and its cross-talk with other types of modification. The tools and methods for prediction and detection of lysine crotonylation were also described.

Fig. 1. Chemical structures of lysine acylations.

Based on their chemical properties, lysine acylations are classified into three groups: the hydrophobic acyl group that extends hydrocarbon chains, including Kac, Kpr, Kbu, Kbz, and Kcr; the polar acyl group includes Kbhb, Khib, and Kla that contain hydroxyl moiety to enable the modified lysine to form hydrogen bonds with other molecules; the acidic acyl group includes Kmal, Ksucc, and Kglu that alter the charge at the lysine residue from +1 to –1 at physiological pH [1].

Fig. 2. The generation of crotonyl-CoA.

SCFAs such as crotonate can be metabolized to crotonyl-CoA by ACCS2 [15]. Besides, SCFA butyrate could be converted into butyryl-CoA through β-oxidation pathway, and further into crotonyl-CoA by BCDH [17]. ACADS and ACOX3 that catalyze conversion of butyryl-CoA to crotonyl-CoA during fatty acid oxidation were demonstrated to be as key crotonyl-CoA producers during endoderm differentiation [18]. In amino acid metabolism of lysine, hydroxylysine, and tryptophan, GCDH catalyzes the oxidation of glutaryl-CoA to crotonyl-CoA and CO₂ [19, 20]. CDYL converts crotonyl-CoA into β-hydroxybutyryl-CoA [22].

Fig. 3. The modulation of protein crotonylation.

Crotonylation has been identified on lysine residues in histone and non-histone proteins. Protein crotonylation was catalyzed by HCT such as p300/CBP [15, 24], MOF [24], and crotonyltransferases including CBP, MOF, and PCAF [9]. Modified crotonyl moiety could be removed by HDCRs HDAC1, 2, 3, 8 [16], SIRT1-3 [34] and decrotonylases HDAC1, 3 [9]. Furthermore, crotonylation acts as docking marks to recruit readers, e.g., DPF family proteins MOZ, DPF2 [38], YEATS domain proteins AF9, ENL [37] and YEATS2 [39].

Fig. 4. Distribution of lys crotonylation and acetylation on the five human histones.

Illustrations of histone Kcr and Kac sites in human cells. Based on PTMs identified in (Tan et al. Cell. 2011) [5].