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
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| 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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Receptores de Neuroquinina-1
/
Subunidades alfa de la Proteína de Unión al GTP Gs
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Arrestinas
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Subunidades alfa de la Proteína de Unión al GTP Gq-G11
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Receptores Acoplados a Proteínas G
Tipo de estudio:
Health_economic_evaluation
Límite:
Animals
/
Humans
Idioma:
En
Revista:
J Biol Chem
Año:
2015
Tipo del documento:
Article