Carboxyl tail

Franci C, Gosling J, Tsou CL, Coughlin SR, Charo IF (1996) Phosphorylation by a G protein-coupled kinase inhibits signaling and promotes internalization of the monocyte chemoattractant protein-1 receptor. Critical role of carboxyl-tail serines/threonines in receptor function. J Immunol 157 5606-5612... 

Fig. 6.1 Schematic representation of the cysteinyl leukotriene 2 (CysLT ) receptor. Ribbon model of this family A G protein-coupled receptor (GPCR) is pictured in its heptahelical configuration. The extracellular amino terminus of the receptor, the transmembrane domains, and the intracellular carboxyl tail extend behind the intracellular palmitoylation site. The putative binding pocket for cysteinyl leukotriene ligands is derived from a rhodopsin model...

The desensitization of most GPCRs appears to be dependent on the carboxyl tail or third intracellular loop regions. For example, the cx -adrenergic (132), the a,g-adrenergic (133), the N-formyl peptide (134), and the M2 muscarinic acetylcholine (135,136) receptors aU contain clusters of residues in the third intracellular loop that are required for desensitization. 

While GRK2, 3, and 5, phosphorylation has been associated with agonist activation of many receptors (44,137), only discrete regions of phosphorylation that are attributable to one specific enzyme appear to be essential for desensitization (122). With respect to the P -adrenergic (138-141), the dopamine D, (122), the p-opioid (142), the 5-opioid (143), the aj -adrenergic (133), the Aj and adenosine (144-146), and the N-formyl peptide (134) receptors, the motifs may be located in the carboxyl tail. 

The desensitization motifs in the dopamine Dj receptor, as an example, may be at least partly located in the proximal carboxyl tail of the receptor f/22). This region may interact with portions of the third intracellular loop to promote desensitization. These structures may also be involved in recycling and trafficking of inactivated receptors (147). 

Fig. 6.3 Amino acid residues required for receptor desensitization and internalization the dopamine Dj receptor example. The substitution of Glu or Thr by Ala results in desensitiza-tion-deficient mutants of the dopamine receptor, but they are stUl able to internalize to some extent. Phosphorylation sites in a 12-amino acid stretch of the distal carboxyl tail ( Thr to Thr and Thr) may be involved in internalization of the receptor. The variant constructs (substitutions by Ala) were generated by site-directed mutagenesis and expressed in cultured Chinese hamster ovary (CHO) cells (122)...

In case of the P -adrenergic receptor, phosphorylation of serine and threonine residues in the carboxyl tail can be shown to be involved in desensitization and internalization (141,156). Other GPCRs—such as the p- and 5-opioid receptors... 

The residues required for internalization, like those implicated in desensitization motifs, do not always meet the requirements for putative sites of kinase-mediated phosphorylation. Among the numerous motifs that have been implicated, an NPXXY motif (154,173) may be required for agonist-induced activation and inter-nahzation of the p -adrenergic receptor, and a dileucine motif in the carboxyl tail of many GPCRs (154) may be involved in internalization of receptors such as the Pj-adrenergic (174) and the vasopressin Via receptors (175). 

Pizard, A., Blaukat, A., MuUer-Esterl, W., Alhenc-Gelas, F., and Rajerison, R. M. (1999) Bradykinin-induced internalization of the human B2 receptor requires phosphorylation of three serine and two threonine residues at its carboxyl tail [in process citation]. J. Biol. Chem. 274, 12738-12747. 

Mutations with similar outcomes have been identified in nonautoimmune autosomal dominant hyperthyroidism (toxic thyroid hyperplasia) (25,26,28,32,33). These variants are located in the third TM (Val509Ala), the seventh TM (Cys672Tyr), and the carboxyl tail (Asp727Glu) regions (34). These variants result in a form of congenital hyperthyroidism that is the germline counterpart of a hyperfunctioning thyroid adenoma, with similar functional characteristics (25,33). 

The phenotypic complexity noted for other GCPR diseases is true also for PTHRl mutations. Opposite clinical manifestations have been reported to result from distinct recessive mutations in the gene. These rare variants present as Eiken syndrome, a distinct entity from JMC and Blomstrand s chondrodysplasia and from enchondromatosis. The skeletal features are opposite those in Blomstrand s chondrodysplasia. The Eiken syndrome variant, resulting in a truncation at position 485, may result in a paradoxical phenotype caused by the consequences of disrupting the carboxyl tail of the receptor (60). 

Lamey, M., Thompson, M., Varghese, G., et al. (2002) Distinct residues in the carboxyl tail mediate agonist-induced desensitization and internalization of the human dopamine D-1 receptor. J. Biol. Chem. 211, 9415-9421. 

Analysis of the primary protein structure of the human 5-HT1B receptor reveals a putative site for palmitoylation, i.e., a cysteine residue located in the short carboxyl tail of the receptor (141). A recombinant c-myc epitope-tagged 5-HT1B receptor was expressed in Sf9 insect cells and palmitoylation of the receptor was demonstrated by metabolic labeling of the cells with [3H]palmitic acid. 

Ali, M. S., Sayeski, P. P., Dirksen, L. B., et al. 1997. Dependence on the motif YIPP for the physical association of Jak2 kinase with the intracellular carboxyl tail of the angiotensin II ATI receptor. J Biol Chem 272 23382-23388. 

The desensitization motifs in the dopamine Di receptor, as an example, may be at least partly located in the proximal carboxyl tail of the receptor [137], It is likely that this region interacts with portions of the third intracellular loop in order to promote desensitization. These structures may also be involved in recycling and trafficking of inactivated receptors [162, 163], A portion of the proximal carboxyl tail of the dopamine Di receptor may contain some of the residues necessary, but not sufficient on their own, for GRK2 mediated desensitization. A motif consisting of a serine or threonine preceded by an acidic amino acid may define the GRK2 recognition sequence [163],... 

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