Abstract
G protein–coupled receptors (GPCRs) are a protein superfamily comprising >800 members that regulate numerous cellular and physiologic responses. GPCRs represent the largest class of therapeutic targets with implications in various diseases. Although advances in GPCR structural and pharmacological research have significantly improved our knowledge of GPCR signaling mechanisms, mapping diverse post-translational modifications (PTMs) of GPCR proteins and understanding their regulatory roles have received much less attention. Mass spectrometry-based proteomics has become the most popular technology for profiling protein PTMs in a systematic manner. Herein we provide an overview of PTM types, locations, crosstalk and dynamic regulation for different GPCRs that are characterized using proteomic and/or biochemical approaches. Our main focus is on glycosylation, phosphorylation, ubiquitination and palmitoylation that are known to modulate receptor folding, biosynthesis, trafficking, dimerization and signaling. Furthermore, we discuss the locations of specific PTM sites in the structure of a given GPCR and its signaling complex to highlight the importance of PTM regulation in the molecular basis of GPCRs, which may shed new light on structure-based drug discovery.
Highlights
G protein-coupled receptors (GPCRs), which are seven-transmembrane proteins, constitute the largest family of cell surface receptors in mammalian cells (>800 in human)
With the advancement of MS-based proteomics technology, a number of posttranslational modifications (PTMs) sites have been mapped to specific receptors stimulated with different ligands, which substantially enhanced our mechanistic understanding of receptor trafficking, activation, internalization and degradation
Certain PTMs are observed in G protein–coupled receptors (GPCRs) structures, providing a molecular basis for in vitro PTM regulation of receptor conformation and interaction with signal transducers
Summary
G protein-coupled receptors (GPCRs), which are seven-transmembrane proteins, constitute the largest family of cell surface receptors in mammalian cells (>800 in human). Post-Translational Modifications of GPCRs review, we provide an overview of PTM types, locations, crosstalk and dynamic regulation for different GPCR proteins that are characterized mainly with proteomic approaches.
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