Molecular structure of mammalian neuropeptide Y: analysis by molecular cloning and computer-aided comparison with crystal structure of avian homologue.

Abstract

Identification and characterization of the cDNA encoding rat neuropeptide Y revealed the nucleotide sequence coding for a 98-amino acid precursor. The deduced amino acid sequence for rat neuropeptide Y is identical to the human peptide and is highly homologous to avian pancreatic polypeptide. The tertiary structure of avian pancreatic polypeptide has been previously derived from crystallographic data by Blundell and coworkers. The homology between neuropeptide Y and avian pancreatic polypeptide preserves all of the residues essential for the maintenance of the tertiary structure. Thus, it has been possible to compute a three-dimensional model of the mammalian neuropeptide, neuropeptide Y, based on the known structure of the avian homologue. This model suggests that neuropeptide preserves a compact tertiary structure characterized by extensive hydrophobic interactions between an N-terminal polyproline-II-like helix and a C-terminal a-helix. The model has been used to identify amino acids residing in key positions within this structure and, thereby, to direct future analysis of neuropeptide Y structure-function relationships.Neurons produce a variety of peptides that are secreted from axons and dendrites and are collectively known as neuropeptides. These peptides arise from larger precursors that are processed enzymatically to yield the mature neuropeptides (1). Neuropeptides are believed to serve as neurotransmitters and neuromodulators (2) by their interaction with specific cell membrane receptors after secretion and have been implicated in the control of behavior and autonomic and motor functions.Understanding the synthesis and secretion of neuropeptides and their mechanism of action requires detailed knowledge of the molecular structure of neuropeptides and neuropeptide precursors. To gain such knowledge, we have combined the methods of molecular cloning of cDNAs complementary to specific mRNAs with computer-aided molecular modeling to deduce both the primary and tertiary structures of the mammalian neuropeptide "neuropeptide Y" (NPY). This neuropeptide was originally identified by chemical means and subsequently purified from porcine brain (3, 4). NPY is widely distributed throughout the mammalian central (5, 6) and peripheral nervous systems (7,8). Central administration has implicated NPY in the control of feeding (9, 10) and in secretion of gonadotrophin-releasing hormone secretion (11). Peripheral administration of NPY induces vasoconstriction in many vascular beds (12-14) and potentiates catecholamine-induced vascular smooth muscle contraction in vitro (15). NPY may play a role in degenerative diseases such as Alzheimer's disease (16). The structure of the precursor of human NPY was recently determined by molecular cloning methods (17).NPY is a member of a larger family that includes the pancreatic polypeptide (18) and peptide YY (19) ( Table 1). In particular, NPY is highly homologous in amino acid sequence to avian pancreatic polypeptide (APP), these two having 19 of the total 36 amino acids in...

Strong evolutionary conservation of neuropeptide Y: sequences of chicken, goldfish, and Torpedo marmorata DNA clones.

“…The only seemingly dramatic replacement occurs at position 11, where Torpedo and goldfish have a polar amino acid, glycine, and all other sequences have a negatively charged amino acid, aspartate. Computer modeling with rat and pig NPY (20,21) has shown that they are compatible with the three-dimensional structure of turkey PP determined by x-ray crystallography (22). We have performed such analyses with the goldfish NPY sequence and found that it too should fit the turkey PP structure.…”

Complete L‐Alanine Scan of Neuropeptide Y Reveals Ligands Binding to Y1 and Y2 Receptors with Distinguished Conformations

“…Since, however, charges of the side chains also contribute to the a-conformation, and positively charged amino acids at the C-terminus increase the helicity (Tonan et al, 1990), the slightly decreased a-helical content of peptides One would not expect an increase of the a-helical content of the [Lys4-Ala4]peptide, however the [Pro*-Ala*]peptide is expected to adopt a more pronounced a-helix. Since, according to the X-ray structure of avian pancreatic polypeptide (Blundell et al, 1981) and molecular dynamic simulations (Allen et al, 1987), the N-terminus is not part of the a-helical segment, the conformational stabilization is the result of either an additional a-helical segment, a helix extension or an increased stabilization of the C-terminal helix as a result of the amino acid exchange. For the increased a-helicity an elongation of the helix is in accordance with the ChouFasman prediction, whereas the lowered helical content of the analogs [AlaZ1]NPY and (Ala8]NPY may be the result of reduced stabilization of the C-terminal helix.…”

“…In recent publications (Allen et al, 1987;MacKerell, 1988, Beck-Sickinger et al, 199Oc) models of the secondary and tertiary structure of neuropeptide Y have been deduced. Each of these models confirms a hairpin structure of neuropeptide Y for its binding conformations to Y, and Y, receptors.…”

“…Starting from the X-ray structure of avian pancreatic polypeptide, a model has been deduced for the three-dimensional structure of porcine NPY (pNPY) and human NPY (hNPY) (Allen et al, 1987;MacKerell, 1988;. Beck-Sickinger et al, 1990~).…”

Modified, cyclic dodecapeptide analog of neuropeptide Y is the smallest full agonist at the human Y2 receptor

“…Neuropeptide Y (NPY) is a 36-peptide amide which exhibits a high homology with the pancreatic polypeptide (PP) and peptide YY (PYY) in both sequence and 3D structure [1,2]. It was isolated from pig brain and sequenced in 1982 [3].…”