Serotonylation: Serotonin Signaling and Epigenetics.

Michael Bader

doi:10.3389/fnmol.2019.00288

Abstract

Serotonylation, the covalent linkage of serotonin to proteins has been discovered more than 60 years ago but only recently the mechanisms and first functions have been elucidated. It has been found that transglutaminases (TG) such as TG2 and the blood coagulation factor XIIIa are the enzymes which catalyze the linkage of serotonin and other monoamines to distinct glutamine (Gln) residues of target proteins. The first target proteins, small G-proteins and extracellular matrix constituents, were found in platelets and are pivotally involved in platelet aggregation and the formation of thrombi. The serotonylation of the same proteins is also involved in insulin secretion and in the proliferation of pulmonary vascular smooth muscle cells and thereby in the pathogenesis of pulmonary arterial hypertension (PAH). Recently histones have been described as targets of serotonylation opening the area of transcriptional control to this posttranslational protein modification. Future studies will certainly reveal further target proteins, signaling pathways, cellular processes, and diseases, in which serotonylation or, more general, monoaminylation is important.

Highlights

IN TRANSGLUTAMINATIONIn the late 1950s the group of Waelsch et al discovered that primary amines can be incorporated into proteins by being covalently linked to glutamine (Gln) residues (Sarkar et al, 1957)
In the meantime at least 8 different transglutaminases (TG) were described, TG1-7 and blood coagulation factor XIII, and it was shown that these enzymes crosslink proteins by linking lysine residues of one protein to glutamines of another (Lorand and Graham, 2003; Eckert et al, 2014; Lai et al, 2017)
We discovered that serotonin is covalently bound to small G-proteins in the cytoplasm by the endogenous transglutaminase TG2 (Walther et al, 2003)

Summary

INTRODUCTION

In the late 1950s the group of Waelsch et al discovered that primary amines can be incorporated into proteins by being covalently linked to glutamine (Gln) residues (Sarkar et al, 1957) These included besides polyamines monoamines such as serotonin, histamine and norepinephrine (Clarke et al, 1959). At normal intracellular concentrations of GTP or GDP TG2 remains in a very compact and inactive configuration and only when intracellular calcium concentrations rise e.g., elicited by the activation of cell surface receptors the enzyme adopts the open state and can transamidate substrates It is not well understood how substrate specificity and the selection of the modified Gln residues is achieved. Accessibility of the Gln residue for the enzyme active site seems to be a major determinant but a specific serotonylation motif has not yet been defined (Lorand and Graham, 2003; Lai et al, 2017)

METHODS

CONCLUDING REMARKS AND FUTURE PERSPECTIVES