Non-specific binding and general cross-reactivity of Y receptor agonists are correlated and should importantly depend on their acidic sectors.
Non-specific binding of Y receptor agonists to intact CHO cells, and to CHO cell or rat brain particulates, is much greater for human neuropeptide Y (hNPY) compared to porcine peptide Y (pPYY), and especially relative to human pancreatic polypeptide (hPP). This binding of hNPY is reduced by alkali cations in preference to non-ionic chaotrope urea, while the much lower non-specific binding of pPYY is more sensitive to urea. The difference could mainly be due to the 10-16 stretch in 36-residue Y agonists (residues 8-14 in N-terminally clipped 34-peptides), located in the sector that contains all acidic residues of physiological Y agonists. Anionic pairs containing aspartate in the 10-16 zone could be principally responsible for non-specific attachments, but may also aid the receptor site binding. Two such pairs are found in hNPY, one in pPYY, and none in hPP. The hydroxyl amino acid residue at position 13 in mammalian PYY and PP molecules could lower conformational plasticity and the non-selective binding via intrachain hydrogen bonding. The acidity of this tract could also be important in agonist selectivity of the Y receptor subtypes. The differences point to an evolutionary reduction of promiscuous protein binding from NPY to PP, and should also be important for Y agonist selectivity within NPY receptor group, and correlate with partial agonism and out-of group cross-reactivity with other receptors.
Department of Molecular Cell Sciences, Univ. of Memphis, Memphis, TN 38152, USA.
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Parker
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Sah
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Balasubramaniam
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Sallee
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Zerbe
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Parker
D020816:Amino Acid Motifs / Q000502:physiology; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites / Q000502:physiology; D016466:CHO Cells; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D003902:Detergents / Q000494:pharmacology; D005768:Gastrointestinal Hormones / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009478:Neuropeptide Y / Q000737:chemistry / Q000378:metabolism; D009479:Neuropeptides / Q000737:chemistry / Q000378:metabolism*; D010191:Pancreatic Polypeptide / Q000737:chemistry / Q000378:metabolism; D010446:Peptide Fragments; D036361:Peptide Hormones / Q000737:chemistry / Q000378:metabolism*; D019894:Peptide YY / Q000737:chemistry / Q000378:metabolism; D010472:Perchlorates / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D017433:Protein Structure, Secondary / Q000502:physiology; D051381:Rats; D017476:Receptors, Neuropeptide Y / Q000819:agonists* / Q000378:metabolism*; D017670:Sodium Compounds / Q000494:pharmacology; D034421:Sus scrofa; D014162:Transfection; D014461:Ultracentrifugation; D014508:Urea / Q000494:pharmacology
D003902:Detergents; D005768:Gastrointestinal Hormones; D009478:Neuropeptide Y; D009479:Neuropeptides; D010446:Peptide Fragments; D036361:Peptide Hormones; D010472:Perchlorates; D017476:Receptors, Neuropeptide Y; D017670:Sodium Compounds; C097212:neuropeptide Y-Y1 receptor; C095889:neuropeptide Y2 receptor; C100568:neuropeptide Y5 receptor; C106655:peptide YY, iodo-Leu(34)-Pro(34)-; D019894:Peptide YY; C061785:peptide YY (3-36); C109491:neuropeptide Y4 receptor; D010191:Pancreatic Polypeptide; D014508:Urea; C031068:sodium perchlorate