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Functional diversity of AT2 receptor orthologues in closely related species.

ABSTRACT: The most striking feature of life is biodiversity. However, mechanisms of biodiversity remain poorly understood, as most protein orthologues of different species are highly homologous in sequence and identical in function. Interestingly, recent evidence has demonstrated heterogeneity for a G protein-coupled angiotensin II (Ang II) type 2 (AT(2)) receptor in both ligand binding and induction of arachidonic acid (AA) release. The present study investigated the properties of AT(2) receptors in closely related species.AT(2) receptors cloned from human, rabbit, rat, and mouse were expressed in Chinese hamster ovary cells (CHO-K1), African green monkey kidney cells (COS-1), and human embryonic kidney (HEK)-293 cells and characterized in ligand binding and signal transductions. Critical residues in rabbit AT(2) receptor attributable to heterogeneity were examined using both gain-of-function and loss-of-function approaches with mutagenesis.The newly cloned rabbit AT(2) receptor exhibits distinct biochemical and biologic properties compared to its highly homologous orthologues (91% in overall amino acid sequence) of rat, mouse, and human. All these orthologues activate SH2 domain-containing phosphatase-1 (SHP-1) and show similar binding affinities for Ang II and AT(2)-specific ligands CGP42112A and PD123319. However, reducing agent dithiothreitol (DTT) inactivates the rabbit orthologue but potentiates the others in ligand binding, a hallmark of AT(2) versus AT(1) receptor subtypes. Most interestingly, rabbit AT(2) receptor, but not the other orthologues, induces AA release in various cell systems when stimulated by both Ang II and CGP42112A, the peptide antagonist. Mutagenesis studies and sequence analyses further indicate that residues His(106), Asp(188), and Thr(293) are responsible for the DTT inactivation and residues Val(209) and Val(249) are partially responsible for AA release.These results deny the coexistence of an additional AT(2) subtype in rabbit proximal tubule cells and demonstrate for the first time the presence of functional diversity for closely related Eutherian orthologues of a G protein-coupled receptor (GPCR) that are more than 90% homologous in the amino acid sequence.

SUBMITTER: Feng YH

PROVIDER: S-EPMC1266296 | biostudies-literature | 2005 May

REPOSITORIES: biostudies-literature

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Functional diversity of AT2 receptor orthologues in closely related species.

Feng Ying-Hong YH Zhou Lingyin L Sun Yan Y Douglas Janice G JG

Kidney international 20050501 5

<h4>Background</h4>The most striking feature of life is biodiversity. However, mechanisms of biodiversity remain poorly understood, as most protein orthologues of different species are highly homologous in sequence and identical in function. Interestingly, recent evidence has demonstrated heterogeneity for a G protein-coupled angiotensin II (Ang II) type 2 (AT(2)) receptor in both ligand binding and induction of arachidonic acid (AA) release. The present study investigated the properties of AT(2 ...[more]

PMID: 15840019

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Project description:BackgroundAkkermansia muciniphila is an important bacterium that resides on the mucus layer of the intestinal tract. Akkermansia muciniphila has a high abundance in human feces and plays an important role in human health.ObjectiveIn this article, 23 whole genome sequences of the Akkermansia genus were comparatively studied.MethodsPhylogenetic trees were constructed with three methods: All amino acid sequences of each strain were used to construct the first phylogenetic tree using the web server of Composition Vector Tree Version 3. The matrix of Genome-to-Genome Distances which were obtained from GGDC 2.0 was used to construct the second phylogenetic tree using FastME. The concatenated single-copy core gene-based phylogenetic tree was generated through MEGA. The single-copy genes were obtained using OrthoMCL. Population structure was assessed by STRUCTURE 2.3.4 using the SNPs in core genes. PROKKA and Roary were used to do pan-genome analyses. The biosynthetic gene clusters were predicted using antiSMASH 4.0. IalandViewer 4 was used to detect the genomic islands.ResultsThe results of comparative genomic analysis revealed that: (1) The 23 Akkermansia strains formed 4 clades in phylogenetic trees. The A. muciniphila strains isolated from different geographic regions and ecological niches, formed a closely related clade. (2) The 23 Akkermansia strains were divided into 4 species based on digital DNA-DNA hybridization (dDDH) values. (3) Pan-genome of A. muciniphila is in an open state and increases with addition of new sequenced genomes. (4) SNPs were not evenly distributed throughout the A. muciniphila genomes. The genes in regions with high SNP density are related to metabolism and cell wall/membrane envelope biogenesis. (5) The thermostable outer-membrane protein, Amuc_1100, was conserved in the Akkermansia genus, except for Akkermansia glycaniphila PytT.ConclusionOverall, applying comparative genomic and pan-genomic analyses, we classified and illuminated the phylogenetic relationship of the 23 Akkermansia strains. Insights of the evolutionary, population structure, gene clusters and genome islands of Akkermansia provided more information about the possible physiological and probiotic mechanisms of the Akkermansia strains, and gave some instructions for the in-depth researches about the use of Akkermansia as a gut probiotic in the future.

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Functional diversity of AT2 receptor orthologues in closely related species.

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Functional diversity of AT2 receptor orthologues in closely related species.

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