Biased Gs versus Gq proteins and ß-arrestin signaling in the NK1 receptor determined by interactions in the water hydrogen bond network.
J Biol Chem
; 290(40): 24495-508, 2015 Oct 02.
Article
em En
| MEDLINE
| ID: mdl-26269596
ABSTRACT
X-ray structures, molecular dynamics simulations, and mutational analysis have previously indicated that an extended water hydrogen bond network between trans-membranes I-III, VI, and VII constitutes an allosteric interface essential for stabilizing different active and inactive helical constellations during the seven-trans-membrane receptor activation. The neurokinin-1 receptor signals efficiently through Gq, Gs, and ß-arrestin when stimulated by substance P, but it lacks any sign of constitutive activity. In the water hydrogen bond network the neurokinin-1 has a unique Glu residue instead of the highly conserved AspII10 (2.50). Here, we find that this GluII10 occupies the space of a putative allosteric modulating Na(+) ion and makes direct inter-helical interactions in particular with SerIII15 (3.39) and AsnVII16 (7.49) of the NPXXY motif. Mutational changes in the interface between GluII10 and AsnVII16 created receptors that selectively signaled through the following 1) Gq only; 2) ß-arrestin only; and 3) Gq and ß-arrestin but not through Gs. Interestingly, increased constitutive Gs but not Gq signaling was observed by Ala substitution of four out of the six core polar residues of the network, in particular SerIII15. Three residues were essential for all three signaling pathways, i.e. the water-gating micro-switch residues TrpVI13 (6.48) of the CWXP motif and TyrVII20 (7.53) of the NPXXY motif plus the totally conserved AsnI18 (1.50) stabilizing the kink in trans-membrane VII. It is concluded that the interface between position II10 (2.50), III15 (3.39), and VII16 (7.49) in the center of the water hydrogen bond network constitutes a focal point for fine-tuning seven trans-membrane receptor conformations activating different signal transduction pathways.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Receptores da Neurocinina-1
/
Subunidades alfa Gs de Proteínas de Ligação ao GTP
/
Arrestinas
/
Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP
/
Receptores Acoplados a Proteínas G
Tipo de estudo:
Health_economic_evaluation
Limite:
Animals
/
Humans
Idioma:
En
Revista:
J Biol Chem
Ano de publicação:
2015
Tipo de documento:
Article