Abstract
G-protein-coupled receptors associate into dimers/oligomers whose function is not well understood. One approach to investigate this issue is to challenge oligomerization by peptides replicating transmembrane domains and to study their effect on receptor functionality. The disruptor peptides are typically delivered by means of cell-penetrating vectors such as the human immunodeficiency virus (HIV) transcription trans-activation protein Tat. In this paper we report a cyclic, Tat-like peptide that significantly improves its linear analogue in targeting interreceptor sequences in the transmembrane space. The same cyclic Tat-like vector fused to a transmembrane region not involved in receptor oligomerization was totally ineffective. Besides higher efficacy, the cyclic version has enhanced proteolytic stability, as shown by trypsin digestion experiments.
Highlights
G-protein-coupled receptors (GPCRs), the most populated gene family in the human genome, are cell-surface receptors known as heptaspanning receptors because they contain seven transmembrane (TM) alpha-helical domains
Class A receptors, the most abundant GPCR group, was assumed for years to act as monomers, but this view has radically changed as many class A GPCRs are expressed as homo- and/or heteroreceptor complexes [9], and there is even in vivo evidence obtained by functional rescue using defective mutants of the gonadotropin releasing hormone receptor [10]
The best tools to decipher the physiological role of GPCR oligomers are peptides that disrupt the quaternary structure and allow exploration of the consequences of heteromer-related loss of function
Summary
G-protein-coupled receptors (GPCRs), the most populated gene family in the human genome, are cell-surface receptors known as heptaspanning receptors because they contain seven transmembrane (TM) alpha-helical domains. Class C GCPRs (e.g., taste, glutamate or γ-aminobutyric acid receptors) are able to form a variety of homo and heteromers (reported as dimers or tetramers) when expressed in heterologous systems. These assemblies are consistent with 3D structural data showing that extracellular domains arrange into dimers [3,4,5,6,7,8]. The first 3D structure of a dimer of a full-length class C receptor, i.e., containing the seven TM helical domains, has been reported for both inactive and active states [12]; this fact raises hopes for similar data coming soon for dimers of class A receptors
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