Post-translational modifications of histone proteins by monoamine neurotransmitters

Abstract

Protein monoaminylation is a biochemical process through which biogenic monoamines (e.g., serotonin, dopamine, histamine, etc.) are covalently bonded to certain protein substrates via Transglutaminase 2, an enzyme that catalyzes the transamidation of primary amines to the γ-carboxamides of glutamine residues. Since their initial discovery, these unusual post-translational modifications have been implicated in a wide variety of biological processes, ranging from protein coagulation to platelet activation and G-protein signaling. More recently, histone proteins - specifically histone H3 at glutamine 5 (H3Q5) - have been added to the growing list of monoaminyl substrates in vivo, with H3Q5 monoaminylation demonstrated to regulate permissive gene expression in cells. Such phenomena have further been shown to contribute critically to various aspects of (mal)adaptive neuronal plasticity and behavior. In this short review, we examine the evolution of our understanding of protein monoaminylation events, highlighting recent advances in the elucidation of their roles as important chromatin regulators.

Figure 1.. Monoamine structures and monoaminylation adducts.

(A) Chemical structures of select monoamine neurotransmitters (serotonin, dopamine, histamine) and the 5-HT analog, 5-PT, that was used for the biorthogonal identification of histone H3 as a substrate for serotonylation in cells. (B) Chemical reaction for protein glutamine monoaminylation by TGM2. (C) Protein glutamine monoaminylation adducts. (D) Location of histone H3 serotonylation on the H3 N-terminus in conjunction with adjacent H3K4me3. (E) Possible chemical adduct for non-endogenous glutamine amphetaminylation.

Figure 2.. Proposed mechanism describing H3Q5ser’s role in permissive transcription.

(Left) H3K4me3 is a permissive modification that is deposited by SET1/MLL1 complexes, and which functions in the recruitment of specific ‘reader’ proteins (e.g., TFIID) to promote transcriptional initiation events in cells. When coupled with H3Q5ser, this dual modification (H3K4me3Q5ser) results in both (Center Left) the enhancement of H3K4me3 ‘reader’ interactions with specific members of the pre-initiation complex (PIC; e.g., TFIID) and (Center Right) inhibition of H3K4 demethylases (e.g., KDM5B), thereby stabilizing permissive transcription at H3K4me3 marked loci. (Right) In addition, we have recently found that TGM2, the “writer” of H3Q5ser, can also “erase” and “re-write” H3 monoaminylation states in cells using alternative monoamine donors, a process that is dependent on fluctuations in the microenvironmental concentrations of the monoamines themselves. Such transitions, in turn, can impact histone “reader” protein recruitment to chromatin, thereby influencing transcription.