Monoaminylation
From Wikipedia, the free encyclopedia
| Part of | Cell |
| Located | Nucleus, Cytoplasm |
| Category | Post-translational Modification |
| 1957 | Heinrich Waelsch & Colleagues Discover calcium-dependent transglutaminases (TGMs) |
| 2003 | Diego Walther & Colleagues Discover protein serotonylation for the first time |
| 2011 | Diego Walther & Colleagues Propose monoaminylation as a novel set of post-translational modifications |
| 2012 | Jakob Vowinckel & Colleagues' Discover protein histaminylation as a novel post-translational modification |
| 2019 | Lorna Farrelly & Colleagues Discover histone serotonylation as a novel post-translational modification |
| 2020 | Ashley Lepack & Colleagues Discover histone dopaminylation as a novel post-translational modification |
| 2021 | Qingfei Zheng & Colleagues Discover histone histaminylation as a novel post-translational modification |
Protein monoaminylation refers to the post-translational modification in which monoamines (i.e., dopamine, serotonin, histamine) are covalently attached to glutamine residues via transamidation. Monoaminylation itself refers to the overall class of post-translational modifications involving monoamines; however, these reactions are further classified by the individual monoamine reactant they describe (i.e., dopaminylation, serotonylation, histaminylation).[1]
Monoaminylation has been reported for both histone and non-histone protein substrates, and thus represents a distinct neuroepigenetic and neuroproteomic regulatory mechanism with various implications in health and disease.[1] Recent studies have unveiled the critical role of monoaminylation in mediating a wide range of physiological processes, be that in the nervous system or beyond.[1][2]
Monoaminylation is known to contribute to several significant diseases, including schizophrenia and various cancers.[1][3][4] To date, notable protein monoaminylation substrates include a number of metabolic enzymes, signal transduction proteins, and cytoskeletal proteins, as well as histone H3.[1][2]
Monoaminylation has been reported in various cell types and tissues, including monoaminergic neurons,[5][6][7][8][9] mammary epithelial cells,[10] vascular smooth muscle,[11] cancer-associated fibroblasts,[12] enterochromaffin cells,[13][14] platelets,[15][16] neutrophils,[17] CD8+ T cells,[18] endothelial cells of the lung,[19] and pancreatic 𝛽-cells.[20] It is also known to influence both tumorigenesis and cancer metastasis, and has been associated with several forms of cancer, including colorectal cancer,[13][14] neuroendocrine prostate cancer,[17] pancreatic cancer,[21] hepatocellular carcinoma,[22][23] and ependymomas (brain cancer).[6]
Protein monoaminylation was first identified in 1957 by Heinrich Waelsch and colleagues at Columbia University. After discovering that primary amines could be covalently incorporated into proteins via transamidation at glutamine residues,[24] the group went on to uncover the enzyme catalyzing these reactions, effectively naming it “transglutaminase” after its function.[25][26]
Despite its discovery in the mid-twentieth century, protein monoaminylation was not investigated as a post-translational modification until 2003, when Diego Walther and colleagues at the Max-Planck-Institute for Molecular Genetics revealed that serotonylation of small GTPases mediates ⍺-granule release during the activation and aggregation of platelets.[16]
Notably, histone monoaminylation was not uncovered as an epigenetic regulatory mechanism until 2019, when Lorna Farrelly and colleagues at the Icahn School of Medicine reported the H3Q5-serotonylation (H3Q5ser) modification for the first time.[27] Later, in 2020, the H3Q5-dopaminylation (H3Q5dop) modification was identified in the striatum by Ashley Lepack and colleagues also at the Icahn School of Medicine.[28] Five years later, Qingfei Zheng and colleagues at Ohio State University discovered the H3Q5-histaminylation (H3Q5his) modification in histaminergic neurons.[9]
Mechanism
Monoaminylation is catalyzed by transglutaminase 2 (TGM2) in a calcium-dependent manner, and relies upon the intracellular bioavailability of monoamine substrates.[2][29] Generally, protein monoaminylation occurs in the cytoplasm; however, histone monoaminylation only occurs within the nucleus.[1][29] Nevertheless, the mechanism for TGM2-catalyzed monoaminylation is identical for both histone and non-histone proteins.[1]
Structurally, Ca2+ binds directly to TGM2 itself and not to the substrate molecule.[29] Once Ca2+ binds to TGM2, a 4 nm relaxation about the major axis of the protein exposes the active site to available substrates.[29][30] The active site itself is composed of a well conserved catalytic triad (Cys277–His335–Asp358) situated within a substrate binding channel, which is bordered by two conserved residues (Trp241 and Trp332) that facilitate catalysis through stabilization of the transition state.[29][31] Once intracellular Ca2+ binds to TGM2 and exposes the substrate binding channel, the glutamine residue of a substrate protein (i.e., histone H3, RhoA) is free to enter the enzyme active site.[1][29] As a transamidation reaction, the mechanism for protein monoaminylation can be summarized in two parts: an initial thioester formation, followed by isopeptide bond formation.
Fig. 1 Mechanism for Protein Monoaminylation
Monoaminylation is a two step, Ca2+-dependent reaction in which TGM2 catalyzes the covalent attachment of a monoamine (ie., dopamine, serotonin, histamine) onto the glutamine residue of a substrate protein. (A) The catalytic cysteine residue (Cys277) of TGM2 facilitates an initial acyl transfer reaction, which is ultimately followed by isopeptide bond formation (B). Common substrate proteins include Histone H3, small GTPases (RhoA, Rab3a), and extracellular matrix proteins (fibronectin).
When intracellular Ca2+ and monoamine concentrations are sufficient, TGM2-catalyzed monoaminylation of substrate proteins can occur.[29] First, the catalytic cysteine residue (Cys277) within the TGM2 active site nucleophilically attacks the 𝛾-carboxamido group of the glutamine residue in an acyl transfer reaction (Fig. 1A), forming a thioester intermediate and releasing one molecule of ammonia (NH3) as a result.[1][29] Next, the deprotonated primary amine of the monoamine substrate nucleophilically attacks the 𝛾-thioester group of the intermediate, forming a stable isopeptide bond and ultimately releasing the enzyme (Fig. 1B).[1][29]