NPXXY motif

The functional role of residue 7.53 in the conserved NPxxY motif in TM7 as a modulator of receptor activation, based on an interaction with Hx8, the segment C-terminal to TM7 that is known to fold into a helical structure (10,54). 

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). 

The carboxyl termini of the 5-HT receptors also contain protein-interacting motifs other than the PDZ ligand. The NPxxY motif located at the junction... 

These residues are conserved in the rhodopsin-like family and form a hydrogen bond network, directly or mediated by water molecules, as revealed by the crystal structure of rhodopsin [25]. This interaction has also been confirmed by site-directed mutagenesis experiments showing that D2.50 and N7.49 have a coordinated substitution pattern in a number of GPGRs, so that when D2.50 changes to N2.50, N7.49 changes to D7.49 [11,26-28]. These three residues contribute to the stabilization of the three dimensional structure of TMl, TM2 and TM7 and their mutation produces serious effects in the function of the receptor. This is the case for the /32 adrenoreceptor [11], TRHR [26], NK2, [27,28], and CBl [29] among others. N7.49 is also part of the well know NPXXY motif that will be discussed in detail later. 

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