The Amino-Terminal Fragment of the Adenylate-Cyclase Activating Polypeptide (Pacap) Receptor Functions as a High-Affinity Pacap Finding Domain

Cao, Yong‐Jiang; Gimpl, Gerald; Fahrenholz, Falk

doi:10.1006/bbrc.1995.2021

Cited by 71 publications

(60 citation statements)

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“…Theoretical predictions of conformation have suggested the possibility that a coiled-coil interaction might exist between extended ␣-helices in ligands and in the distal amino-terminal tail domain of receptors in this family (32). The critical importance of this region has also been experimentally supported by receptor truncation, site-directed mutagenesis, and chimeric receptor studies (9,(33)(34)(35)(36)(37)(38). Affinity labeling studies have provided direct experimental data to support this interpretation.…”

Section: Discussionmentioning

confidence: 97%

Identification of Two Pairs of Spatially Approximated Residues within the Carboxyl Terminus of Secretin and Its Receptor

Dong

Asmann

Zang

et al. 2000

Journal of Biological Chemistry

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The carboxyl-terminal domains of secretin family peptides have been shown to contain key determinants for high affinity binding to their receptors. In this work, we have examined the interaction between carboxyl-terminal residues within secretin and the prototypic secretin receptor. We previously utilized photoaffinity labeling to demonstrate spatial approximation between secretin residue 22 and the receptor domain that includes the first 30 residues of the amino terminus (Dong, Detailed understanding of the molecular basis of ligand binding and receptor activation will be the key to facilitate the rational design of new drugs. Guanine nucleotide-binding protein (G protein)-coupled receptors represent the largest group of plasma membrane receptors and include many potentially important targets for therapeutic agents, making this superfamily an ideal focus for these efforts.MThis superfamily includes receptor families that share sequence homologies and structural similarities of their natural ligands. Among these is the recently described class II family that includes receptors for secretin, calcitonin, parathyroid hormone, glucagon, vasoactive intestinal polypeptide, and pituitary adenylate cyclase-activating polypeptide (3, 4). The natural agonist ligands of these receptors have helical domains in both carboxyl-terminal and amino-terminal regions (5, 6) and have binding determinants that are spread throughout their entire length (3, 4, 7). The theme is emerging that aminoterminal regions of these peptides contain key determinants for receptor selectivity, whereas carboxyl-terminal regions contain determinants for high affinity binding (8, 9). Of note, the carboxyl-terminal regions of some of the members of this family may even be interchanged while maintaining high affinity binding (9). This feature supports the likely general relevance of the observations in the current work to the entire class II family.We recently used affinity labeling to demonstrate spatial approximation between a photolabile residue within the carboxyl-terminal half of secretin (position 22) and a 30-residue segment at the distal amino terminus of its prototypic secretin receptor (1). Of interest, the amino-terminal tail of the class II G protein-coupled receptor family has remarkable structural features and major functional importance (3,4). This receptor domain is moderately large, containing greater than 110 residues, with six conserved Cys residues and key disulfide bonds (10). Chemical reduction and treatment with sulfhydryl-reactive compounds have had substantial negative impact on these receptors (10 -12). Truncation, site-directed mutagenesis, and chimeric receptor studies have also supported the critical role of this domain in the function of this receptor family (9,13).In the present work, we have extended our understanding of the siting of secretin residue 22 when bound to its receptor by defining a receptor residue adjacent to it. We have also established spatial approximation between another residue closer to the carboxyl ter...

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Section: Discussionmentioning

confidence: 97%

Identification of Two Pairs of Spatially Approximated Residues within the Carboxyl Terminus of Secretin and Its Receptor

Dong

Asmann

Zang

et al. 2000

Journal of Biological Chemistry

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“…Other examples in which the N-terminal domain of a GPCR binds ligand are the metabotropic glutamate receptor (33,34,51), the luteinizing hormone/human chorionic gonadotropin receptor (29), the follicle stimulating hormone receptor (28), the pituitary adenylate cyclase-activating polypeptide receptor (52), the PTH receptor (31), and the glucagon-like peptide-1 receptor (32), the last two also being members of the receptor subfamily to which the CRF receptor belongs. The glucagonlike peptide-1R, expressed and purified as a soluble protein in Chinese hamster lymphoblastoma cells, exhibited lower binding affinity compared with the native receptor, and lost activity after reduction of the disulfide bonds (32).…”

Section: Discussionmentioning

confidence: 99%

Expression, Purification, and Characterization of a Soluble Form of the First Extracellular Domain of the Human Type 1 Corticotropin Releasing Factor Receptor

Perrin¹,

Fischer²,

Kunitake³

et al. 2001

Journal of Biological Chemistry

108

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Corticotropin releasing factor (CRF), 1 a 41-amino acid peptide, was identified initially on the basis of its primary role in the activation of the hypothalamic-pituitary-adrenal in response to stress. The CRF family of ligands includes sauvagine from frog and urotensin from fish as well as the additional mammalian family members, urocortin (1, 2), urocortin II (3, 4), and urocortin III (4, 5). Broader roles for CRF and its ligand family now involve effects on the cardiovascular, reproductive, gastrointestinal, immune, and central nervous systems (6 -8).The action of CRF and related ligands is initiated by binding to their receptors, which transduce an increase in intracellular cAMP. Thus far, two receptors, CRFR1 and CRFR2, have been cloned in mammals (9 -15). Homologous receptors have been identified in chicken (16), fish (17), and Xenopus (18) and a third receptor, CRFR3, with high levels of sequence identity to CRFR1, has recently been cloned in catfish (17). Both CRFR1 and CRFR2 exist as multiple splice variants and belong to the type B 7-transmembrane receptor family that includes receptors for growth hormone releasing factor, secretin, calcitonin, vasoactive intestinal peptide, glucagon, glucagon-like peptide, and parathyroid hormone (PTH). Receptors for the CRF ligand family have been characterized in the central nervous system, pituitary, gastrointestinal tract, epididymis, heart, gonads, and adrenals (6).The affinities of CRF and urocortin in binding to CRFR1 are nearly the same but in binding to CRFR2, urocortin is ϳ10 times more potent than CRF (19). Both urocortins II and III are highly selective in binding and activating CRFR2 compared with CRFR1 (4, 5). A synthetic peptide antagonist, astressin, binds with equally high affinity to CRFR1 and CRFR2 (19,20).The CRF receptor family consists of proteins with a relatively large first extracellular domain (ECD-1). Mutagenesis studies have identified regions of the CRF receptors that are implicated in differential recognition of agonists and antagonists, as well as in governing the ligand selectivity of the two types of receptors (21-25). We showed that a chimeric receptor in which the ECD-1 of CRFR1 replaced the ECD of the activin receptor, a single transmembrane receptor kinase (26), was capable of high affinity binding to both astressin and urocortin (21). The mode of receptor activation was explored by our study of a tethered peptide-receptor chimera in which the first 16 amino acids of CRF were substituted for the ECD-1 of CRFR1 (CRF (1-16)/R1 ⌬N ) (27). This chimera displayed continual signaling suggesting that the N-terminal third of CRF, when presented in proximity to the receptor, is able to cause activation.Biochemical characterizations of soluble ECD-1s include those of receptors for follicle stimulating hormone (28), luteinizing hormone/human chorionic gonadotropin (29), calcium (30), PTH (31), glucagon-like peptide-1 (32), and glutamate (33). The ECD-1 of the metabotropic glutamate receptor has

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“…The first radioactive peak represented the monoiodinated peptides ( Plasmid construction and transient transfection. The construction of the expression plasmid pPACAPR was performed as previously described (Cao et al, 1995). This plasmid encodes an N-terminal c-myc-epitope tag, an IgA protease cleavage site, and the full-length PACAP type I receptor.…”

Section: Methodsmentioning

confidence: 99%

“…Crude membranes from transfected COS cells and pig brain were prepared as previously described (Cao et al, 1994(Cao et al, , 1995. The designated membrane fragments were frozen in aliquots and stored at -70°C.…”

Section: Methodsmentioning

confidence: 99%

“…Some structural requirements for the occupancy of the PACAP type I receptors have been reported and led to the development of receptor antagonists Vandermeers et al, 1992;Bitar et al, 1994). By using chemical modification and deletion mutagenesis, we have previously demonstrated that the N-terminal fragment of the PACAP type I receptor contains a major binding site for its ligand (Cao et al, 1994(Cao et al, , 1995. In the present study, we used photoaffinity labeling, which provides a method to directly identify contact regions of a receptor and its ligand.…”

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confidence: 97%

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Photoaffinity Labeling Analysis of the Interaction of Pituitary Adenylate‐Cyclase‐Activating Polypeptide (PACAP) with the PACAP Type I Receptor

Cao

Kojro

Gimpl

et al. 1997

European Journal of Biochemistry

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To identify residues and domains of the peptide hormone pituitary adenylate-cyclase-activating polypeptide (PACAP) that interact with the type I receptor, two photoreactive analogues of PACAP-( 1-27)-peptide were synthesized using solid-phase peptide synthesis. Phe6 or Tyr22 within the PACAP sequence were replaced by p-benzoyl-L-phenylalanine (Bz-Phe) thus creating two PACAP derivatives with a photoreactive amino acid in either the disordered N-terminal or the helical C-terminal part of the peptide. The ligand-binding properties and the efficiencies of these peptide analogues as photolabels were tested for pig brain PACAP receptors.

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The Amino-Terminal Fragment of the Adenylate-Cyclase Activating Polypeptide (Pacap) Receptor Functions as a High-Affinity Pacap Finding Domain

Cited by 71 publications

References 0 publications

Identification of Two Pairs of Spatially Approximated Residues within the Carboxyl Terminus of Secretin and Its Receptor

Identification of Two Pairs of Spatially Approximated Residues within the Carboxyl Terminus of Secretin and Its Receptor

Expression, Purification, and Characterization of a Soluble Form of the First Extracellular Domain of the Human Type 1 Corticotropin Releasing Factor Receptor

Photoaffinity Labeling Analysis of the Interaction of Pituitary Adenylate‐Cyclase‐Activating Polypeptide (PACAP) with the PACAP Type I Receptor

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