Mutagenesis of human neuropeptide Y/peptide YY receptor Y2 reveals additional differences to Y1 in interactions with highly conserved ligand positions
2010 (English)In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 163, no 1-3, 120-129 p.Article in journal (Refereed) Published
Neuropeptide Y (NPY) and peptide YY (PYY) share similar to 70% of their 36 amino acids and bind to the same three human receptor subtypes, Y1, Y2 and Y5, even though these receptors only share similar to 30% sequence identity Based on our previous investigation of human Y1 we describe here a mutagenesis study of three corresponding positions in human Y2, i e Tyr(2 64), Val(6 58) and Tyr(7 31) Pharmacological characterization was performed with the four peptide agonists PYY, NPY, PYY(3-36) and NPY(13-36) as well as the non-peptide antagonist BIIE0246 Results from mutants where Tyr(2 64) has been substituted by Ala suggest that Tyr(2 64) is involved in the interaction with all investigated ligands whereas position Tyr(7 31) seems to be more important for interaction with the truncated peptide PYY(3-36) than with intact NPY Surprisingly, substitution of Tyr(7 31) with His, the corresponding residue in Y1, resulted in total loss of binding of iodinated porcine PYY The third position. Val(6 58), did not influence binding of any of the ligands. These findings differ from those obtained for Y1 where Ala substitution resulted in lost or changed binding for each of the three positions. Although Tyr(2 64) and Tyr(7 31) in Y2 are involved in ligand binding, their interactions with the peptide ligands seem to be different from the corresponding positions in Y1 This suggests that the receptor-ligand interactions have changed during evolution after Y1 and Y2 arose from a common ancestral receptor.
Place, publisher, year, edition, pages
2010. Vol. 163, no 1-3, 120-129 p.
Site-directed mutagenesis, G-protein coupled receptor, Three dimensional model, Evolution
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-135756DOI: 10.1016/j.regpep.2010.04.011ISI: 000280050000018OAI: oai:DiVA.org:uu-135756DiVA: diva2:375574
Manuscript title: Investigation of receptor-ligand interactions of the human neuropeptide Y receptor Y2 by site-directed mutagenesis: comparison with the structurally divergent Y1 subtype2010-12-082010-12-082014-05-08Bibliographically approved