title: How adenylate cyclase choreographs the pas de deux of the receptors heteromerization dance.
abstract: Our work suggests that heteromer formation, mainly involves linear motifs (LMs) found in disordered regions of proteins. Local disorder imparts plasticity to LMs. Most molecular recognition of proteins occurs between short linear segments, known as LMs. Interaction of short continuous epitopes is not constrained by sequence and has the advantage of resulting in interactions with micromolar affinities which suit transient, reversible complexes such as receptor heteromers. Electrostatic interactions between epitopes of the G-protein coupled receptors (GPCR) involved, are the key step in driving heteromer formation forward. The first step in heteromerization, involves phosphorylating Ser/Thr in an epitope containing a casein kinase 1/2-consensus site. Our data suggest that dopaminergic neurotransmission, through cAMP-dependent protein kinase A (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.
authors: Structural Biology Unit, Integrative Neuroscience Branch, NIDA IRP, NIH, MD, United States. awoods@mail.nih.gov
authors: A S
authors: AS
authors: Woods
authors: S N
authors: SN
authors: Jackson
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D000939:Epitopes / Q000378:metabolism; D008958:Models, Molecular; D010766:Phosphorylation; D011487:Protein Conformation; D055503:Protein Multimerization / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*
chemical_list: D000939:Epitopes; D043562:Receptors, G-Protein-Coupled; D017868:Cyclic AMP-Dependent Protein Kinases; D000262:Adenylyl Cyclases