Dopaminylation

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Dopaminylation
Post-translational modification in which dopamine is covalently attached to glutamine residues via reactions catalyzed by TGM2.
Biochemical Reaction
Part ofCell
LocatedNucleus, Cytoplasm
CategoryPost-translational Modification
Central Functions
Promotes Drug-Seeking Behaviors
Regulates Cocaine-Induced Gene Expression Programs
Modulation of Stress-Induced Epigenetic Signatures
Key Enzymes
Known Substrates
Discovered
2011 Diego Walther & Colleagues
Propose monoaminylation as a novel set of post-translational modifications
2020 Ashley Lepack & Colleagues
Discover histone dopaminylation as a novel post-translational modification
2024 Nan Zhang & Colleagues
Develop a bicyclononyne (BCN)-probe for chemical proteomic profiling of dopaminylation in cells

Protein dopaminylation refers to the post-translational modification in which dopamine is covalently attached to glutamine residues via transamidation. In general, protein monoaminylation 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).

Dopaminylation 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. Recent studies have unveiled a critical role for dopaminylation in mediating a wide range of physiological processes, be that in the nervous system or beyond.[1][2] Dopaminylation is known to contribute to several significant neuropsychiatric disorders (i.e., drug addiction, substance use disorder),[3][4] and has also been found to promote lung regeneration through suppression of ferroptosis.[2]

To date, the dopaminylation proteome has remained largely unexplored due to a lack of efficient pan-specific antibodies targeting dopaminylated glutamine.[5] Notably, histone H3, fibronectin, and TPI1 were the only identified targets of protein dopaminylation until 2024, when a recently developed bicyclononyne (BCN)-containing probe was successfully applied in chemical proteomic profiling of the dopaminylation proteome in cancer cells.[1][5] Herein, authors present emerging evidence suggesting that 425 proteins possessed dopaminylation sites in a colorectal cancer cell line (ie., HCT 116 cells).[5] The advent of this BCN probe is anticipated to enable more extensive investigations of dopaminylation in 2026, and may facilitate a substantial increase in studies on the functions of dopaminylation in both health and disease. Nevertheless, dopaminylation has been reported in a variety of tissues, including the nucleus accumbens (NAc),[3] ventral tegmental area (VTA),[4] amygdala,[6] and in the vascular endothelial niche.[2] Dopaminylation is known to influence both drug-seeking behaviors (i.e., cocaine, heroin) and differential gene expression programs associated with substance abuse,[3][4] and has been associated with changes in epigenetic signatures within the limbic system following early-life stressful social experience (SSE) in rats.[6]

Protein monoaminylation was first identified in 1957 by Heinrich Waelsch and colleagues at Columbia University.[7] After discovering that primary amines could be covalently incorporated into proteins via transamidation at glutamine residues,[7] the group went on to uncover the enzyme catalyzing these reactions, effectively naming it “transglutaminase” after its function.[8][9]

Despite its discovery in the mid-twentieth century, 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.[10]

Notably, 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.[11] 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.[12] Five years later, Qingfei Zheng and colleagues at Ohio State University discovered the H3Q5-histaminylation (H3Q5his) modification in the posterior hypothalamic tuberomammillary nucleus (TMN).[13]

In 2024, Nan Zhang and colleagues at Ohio State University developed a bicyclononyne (BCN)-containing probe to address the lack of efficient pan-specific antibodies targeting dopaminylated glutamine.[5] Herein, the group successfully applied the BCN-probe in chemical proteomic profiling of the dopaminylation proteome in a colorectal cancer cell line (ie., HCT 116 cells), identifying over 400 dopaminylated proteins and providing extensive pathway enrichment data following their analyses using the Kyoto Encyclopedia of Genes and Genomes (KEGG) database.[5]

Mechanism

Dopaminylation is catalyzed by transglutaminase 2 (TGM2) in a calcium-dependent manner, and relies upon the intracellular bioavailability of dopamine substrates.[14][15] Generally, protein dopaminylation occurs in the cytoplasm; however, histone dopaminylation only occurs within the nucleus.[1][15] Nevertheless, the mechanism for TGM2-catalyzed dopaminylation is identical for both histone and non-histone proteins alike.[1]

Structurally, Ca2+ binds directly to TGM2 itself and not to the substrate molecule.[14] Once Ca2+ binds to TGM2, a 4 nm relaxation about the major axis of the protein exposes the active site to available substrates.[14][16] 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.[14][17] Once intracellular Ca2+ binds to TGM2 and exposes the substrate binding channel, the glutamine residue of a substrate protein (i.e., histone H3, TPD1) is free to enter the enzyme active site.[1][14] As a transamidation reaction, the mechanism for protein dopaminylation can be summarized in two parts: an initial thioester formation, followed by isopeptide bond formation.

Fig. 1 Mechanism for Protein Dopaminylation
Dopaminylation is a two step, Ca2+-dependent reaction in which TGM2 catalyzes the covalent attachment of dopamine onto the glutamine residue of a substrate protein (i.e., Histone H3, TPI1). (A) The catalytic cysteine residue (Cys277) of TGM2 facilitates an initial acyl transfer reaction, which is ultimately followed by isopeptide bond formation (B).

When intracellular Ca2+ and dopamine concentrations are sufficient, TGM2-catalyzed dopaminylation of substrate proteins can occur.[14] First, the catalytic cysteine residue (Cys277) in 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][14] Next, the deprotonated primary amine of the dopamine substrate nucleophilically attacks the 𝛾-thioester group of the intermediate, forming a stable isopeptide bond and ultimately releasing the enzyme (Fig. 1B).[1][14]

Functions

See Also

References

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