How adenylate cyclase choreographs the pas de deux of the receptors heteromerization dance

Abstract

Our work suggests that heteromer formation, mainly involves linear motifs found in disordered regions of proteins. Local disorder imparts plasticity to linear motifs. Many molecular recognition of proteins occur between short linear segments, known as LMs. Interaction of short continuous epitopes are not constrained by sequence and have the advantage of resulting in interactions with micromolar affinities which suites transient, reversible complexes such as receptor heteromers. Electrostatic Interactions between epitopes of the GPCR involved, is the Key step in driving heteromer formation forward. The first step in heteromerization, involves phosphorylating the Ser/Thr in an epitope containing a casein kinase 1/2 (CK1/2)-consensus site. Our data suggests that dopaminergic neurotransmission, through cAMP dependent PKA slows down heteromerization. The negative charge, acquired by the phosphorylation of a Ser/Thr in a PKA consensus site in the Arg rich epitope, affects the activity of the receptors involved in heteromerization by causing allosteric conformational changes, due to the repulsive effect generated by the negatively charged phosphate. In addition to modulating heteromerization, it affects the stability of the heteromers’ interactions and their binding affinity. So here we have an instance where phosphorylation is not just an on/off switch, instead by weakening the noncovalent bond, heteromerization acts like a rheostat that controls the stability of the heteromer through activation or inhibition of adenylate cyclase by the neurotransmitter Dopamine depending on which Dopamine receptor it docks at.

Distribution of 5-HT1F Receptors in Monkey Vestibular and Trigeminal Ganglion Cells

“…Studies suggest that heterodimerization between 5-HT 1B and 5-HT 1D receptors may require a co-translational or specific cellular mechanism and appears to be favored over homodimerization when these subtypes are co-expressed ( 43 ). Although there is a dearth of information on oligomerization of 5-HT 1F receptors, recent evidence indicates that phosphorylation by PKA is involved in regulating the stability of heteromers of dopamine and adenosine G-protein-coupled receptors through interactions at short linear motifs on the receptor subunit proteins ( 64 ). Hence, dynamic regulation of heteromerization and oligomerization may be a factor in understanding both fluctuations within and individual and inter individual differences in effects of ligands.…”

Evolutionary pattern in the OXT-OXTR system in primates: Coevolution and positive selection footprints

“…However, we opted for a more conservative approach to evaluate the OXTR changes. We took into account functional information for OXTR intracellular domains (loops and C-terminal portion) to search for phosphorylation posttranslational modifications, as they are very important for GPCR regulation, as well as dimerization (24,56,57). Three available software packages were used to obtain a consensus result: PPSP 1.06 Prediction of PK-specific Phosphorylation site (58), NetPhosK 1.0 (59), and GPS 2.1 Group-based Prediction System (58).…”

G protein-coupled receptor-receptor interactions give integrative dynamics to intercellular communication

“…In this RM, a reciprocal inter action between D 2 and A 2A receptors also exists, as D 2 receptor can inhibit the A 2A -induced increase in cyclic AMP (cAMP) accumulation via G i/o at the level of the adenylate cyclase (Kull et al, 1999). As discussed by Woods and Jackson (2013), in this heterodimer, the first step driving heteromerization involves the phosphorylation of the serine/threonine in an epitope containing a casein kinase 1/2-consensus site, and dopaminergic neurotransmission, through cAMP-dependent protein kinase A (PKA), slows down heteromerization. In addition, the negative charge, acquired by phosphorylating a serine/threonine in a PKA consensus site in the arginine-rich epitope, affects the activity of the receptors involved in heteromerization by causing allosteric conformational changes, due to the repulsive effect generated by the negatively charged phosphate, thus modulating heteromerization and affecting the stability of heteromers' interactions and their binding affinity.…”