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Molecular evolution of the neuropeptide S receptor.

Pitti T, Manoj N - PLoS ONE (2012)

Bottom Line: Phylogenetic analyses revealed that the NPSR is most closely related to the invertebrate cardioacceleratory peptide receptor (CCAPR) and the group of vasopressin-like receptors.Gene structure features were congruent with the phylogenetic clustering and supported the orthology of NPSR to the invertebrate NPSR-like and CCAPR.The data can facilitate experimental studies aiming at deciphering the common features as well as those related to ligand binding and signal transduction processes specific to the NPSR.

View Article: PubMed Central - PubMed

Affiliation: Department of Biotechnology, Indian Institute of Technology Madras, Chennai, India.

ABSTRACT
The neuropeptide S receptor (NPSR) is a recently deorphanized member of the G protein-coupled receptor (GPCR) superfamily and is activated by the neuropeptide S (NPS). NPSR and NPS are widely expressed in central nervous system and are known to have crucial roles in asthma pathogenesis, locomotor activity, wakefulness, anxiety and food intake. The NPS-NPSR system was previously thought to have first evolved in the tetrapods. Here we examine the origin and the molecular evolution of the NPSR using in-silico comparative analyses and document the molecular basis of divergence of the NPSR from its closest vertebrate paralogs. In this study, NPSR-like sequences have been identified in a hemichordate and a cephalochordate, suggesting an earlier emergence of a NPSR-like sequence in the metazoan lineage. Phylogenetic analyses revealed that the NPSR is most closely related to the invertebrate cardioacceleratory peptide receptor (CCAPR) and the group of vasopressin-like receptors. Gene structure features were congruent with the phylogenetic clustering and supported the orthology of NPSR to the invertebrate NPSR-like and CCAPR. A site-specific analysis between the vertebrate NPSR and the well studied paralogous vasopressin-like receptor subtypes revealed several putative amino acid sites that may account for the observed functional divergence between them. The data can facilitate experimental studies aiming at deciphering the common features as well as those related to ligand binding and signal transduction processes specific to the NPSR.

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Multiple alignment of functionally divergent sites in the NPSR and vasopressin-like receptors.Samplings of selected functional divergence-related positions in the region starting from TM2 to the end of ECL3 are shown. Amino acid positions (marked on top) are identified by Ballesteros-Weinstein numbering corresponding to the residue position in human NPSR. Contiguous blocks of conserved residues in the NPSR are shown within hollow boxes. Residues associated with Type I and II divergence are marked in blue background and red background, respectively (Data S3).
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pone-0034046-g003: Multiple alignment of functionally divergent sites in the NPSR and vasopressin-like receptors.Samplings of selected functional divergence-related positions in the region starting from TM2 to the end of ECL3 are shown. Amino acid positions (marked on top) are identified by Ballesteros-Weinstein numbering corresponding to the residue position in human NPSR. Contiguous blocks of conserved residues in the NPSR are shown within hollow boxes. Residues associated with Type I and II divergence are marked in blue background and red background, respectively (Data S3).

Mentions: The NPSR/NPSR-like sequences range from 370 to 394 amino acids in length. The two NPSR-like sequences share pairwise sequence identities in the range 35–40% across the entire sequence and 40 to 52% in the transmembrane helices (TM), in a multiple alignment with NPSR homologs. Several conserved sequence motifs that may play an important role in function were identified based on alignment of the identified sequences. Since the structure-function relationship in the receptor is very poorly studied, a comparison of regions in the sequence corresponding to known functional regions in the better-studied paralogous vasopressin-like receptor sequences was carried out to identify common as well as selective receptor positions. In all subsequent analyses and comparisons of residue positions, the residue numbering includes Ballesteros-Weinstein numbers in superscript [53], [54]. The topology of the regions comprising the three structural parts, namely the TM, the extracellular loops (ECL) and the intracellular loops (ICL) have been assigned from the prediction of TM regions for the human NPSR entry [GenBank: NP_997055] using the TMHMM program (Figure 2, Figure S3). Examples of common peptide GPCR conserved motifs include LxxxD (902.46–942.50) in TM2, CWxP (2866.47–2896.50) in TM6, NPxxY (3267.49–3307.53) in TM7. Cysteine residues (C1213.25, C1974.76) responsible for the formation of disulfide bond between extracellular loops (ECL1 and 2) are also conserved [55]–[57]. Examination of the sequence alignment indicates that these positions are completely conserved in the NPSR/NPSR-likes and the vasopressin-like receptors. Two conserved motifs WXFG and DXXCR in ECL1 have been reported to be crucial for ligand binding and signaling in the neuropeptide receptors [58]. In the vertebrate NPSR, these regions correspond to highly conserved WRFTG (1082.64–1122.68) and DLVCR (1183.22–1223.26) motifs (Figure 3). However, the NPSR-like sequences appear to have a modified HRFTX motif in place of WRFTG. Other functionally important regions for agonist recognition in the vasopressin-like receptors includes the completely conserved regions FQVLPQ at the end of TM2 and motif PWG in the ECL2 [56], [59], [60]. However, the corresponding regions in the NPSR contains different, albeit highly conserved motifs VNILTD (1002.56–1052.61) and DSY (2044.83–2064.85), respectively (Figure 3).


Molecular evolution of the neuropeptide S receptor.

Pitti T, Manoj N - PLoS ONE (2012)

Multiple alignment of functionally divergent sites in the NPSR and vasopressin-like receptors.Samplings of selected functional divergence-related positions in the region starting from TM2 to the end of ECL3 are shown. Amino acid positions (marked on top) are identified by Ballesteros-Weinstein numbering corresponding to the residue position in human NPSR. Contiguous blocks of conserved residues in the NPSR are shown within hollow boxes. Residues associated with Type I and II divergence are marked in blue background and red background, respectively (Data S3).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3316597&req=5

pone-0034046-g003: Multiple alignment of functionally divergent sites in the NPSR and vasopressin-like receptors.Samplings of selected functional divergence-related positions in the region starting from TM2 to the end of ECL3 are shown. Amino acid positions (marked on top) are identified by Ballesteros-Weinstein numbering corresponding to the residue position in human NPSR. Contiguous blocks of conserved residues in the NPSR are shown within hollow boxes. Residues associated with Type I and II divergence are marked in blue background and red background, respectively (Data S3).
Mentions: The NPSR/NPSR-like sequences range from 370 to 394 amino acids in length. The two NPSR-like sequences share pairwise sequence identities in the range 35–40% across the entire sequence and 40 to 52% in the transmembrane helices (TM), in a multiple alignment with NPSR homologs. Several conserved sequence motifs that may play an important role in function were identified based on alignment of the identified sequences. Since the structure-function relationship in the receptor is very poorly studied, a comparison of regions in the sequence corresponding to known functional regions in the better-studied paralogous vasopressin-like receptor sequences was carried out to identify common as well as selective receptor positions. In all subsequent analyses and comparisons of residue positions, the residue numbering includes Ballesteros-Weinstein numbers in superscript [53], [54]. The topology of the regions comprising the three structural parts, namely the TM, the extracellular loops (ECL) and the intracellular loops (ICL) have been assigned from the prediction of TM regions for the human NPSR entry [GenBank: NP_997055] using the TMHMM program (Figure 2, Figure S3). Examples of common peptide GPCR conserved motifs include LxxxD (902.46–942.50) in TM2, CWxP (2866.47–2896.50) in TM6, NPxxY (3267.49–3307.53) in TM7. Cysteine residues (C1213.25, C1974.76) responsible for the formation of disulfide bond between extracellular loops (ECL1 and 2) are also conserved [55]–[57]. Examination of the sequence alignment indicates that these positions are completely conserved in the NPSR/NPSR-likes and the vasopressin-like receptors. Two conserved motifs WXFG and DXXCR in ECL1 have been reported to be crucial for ligand binding and signaling in the neuropeptide receptors [58]. In the vertebrate NPSR, these regions correspond to highly conserved WRFTG (1082.64–1122.68) and DLVCR (1183.22–1223.26) motifs (Figure 3). However, the NPSR-like sequences appear to have a modified HRFTX motif in place of WRFTG. Other functionally important regions for agonist recognition in the vasopressin-like receptors includes the completely conserved regions FQVLPQ at the end of TM2 and motif PWG in the ECL2 [56], [59], [60]. However, the corresponding regions in the NPSR contains different, albeit highly conserved motifs VNILTD (1002.56–1052.61) and DSY (2044.83–2064.85), respectively (Figure 3).

Bottom Line: Phylogenetic analyses revealed that the NPSR is most closely related to the invertebrate cardioacceleratory peptide receptor (CCAPR) and the group of vasopressin-like receptors.Gene structure features were congruent with the phylogenetic clustering and supported the orthology of NPSR to the invertebrate NPSR-like and CCAPR.The data can facilitate experimental studies aiming at deciphering the common features as well as those related to ligand binding and signal transduction processes specific to the NPSR.

View Article: PubMed Central - PubMed

Affiliation: Department of Biotechnology, Indian Institute of Technology Madras, Chennai, India.

ABSTRACT
The neuropeptide S receptor (NPSR) is a recently deorphanized member of the G protein-coupled receptor (GPCR) superfamily and is activated by the neuropeptide S (NPS). NPSR and NPS are widely expressed in central nervous system and are known to have crucial roles in asthma pathogenesis, locomotor activity, wakefulness, anxiety and food intake. The NPS-NPSR system was previously thought to have first evolved in the tetrapods. Here we examine the origin and the molecular evolution of the NPSR using in-silico comparative analyses and document the molecular basis of divergence of the NPSR from its closest vertebrate paralogs. In this study, NPSR-like sequences have been identified in a hemichordate and a cephalochordate, suggesting an earlier emergence of a NPSR-like sequence in the metazoan lineage. Phylogenetic analyses revealed that the NPSR is most closely related to the invertebrate cardioacceleratory peptide receptor (CCAPR) and the group of vasopressin-like receptors. Gene structure features were congruent with the phylogenetic clustering and supported the orthology of NPSR to the invertebrate NPSR-like and CCAPR. A site-specific analysis between the vertebrate NPSR and the well studied paralogous vasopressin-like receptor subtypes revealed several putative amino acid sites that may account for the observed functional divergence between them. The data can facilitate experimental studies aiming at deciphering the common features as well as those related to ligand binding and signal transduction processes specific to the NPSR.

Show MeSH
Related in: MedlinePlus