Role of the His273 Located in the Sixth Transmembrane Domain of the Angiotensin II Receptor Subtype AT2 in Ligand–Receptor Interaction

Turner, Cortney A.; Cooper, Shannon; Pulakat, Lakshmi

doi:10.1006/bbrc.1999.0207

Cited by 17 publications

(12 citation statements)

References 32 publications

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“…[32][33][34] Numerous studies have identified different AT2R regions responsible for the interaction with other proteins involved in AT2R activation or regulation. Among these regions, the fifth and sixth transmembrane domains were shown to directly interact with the agonist Ang II, [35][36][37][38] and the third intracellular loop 38 -40 and the cytoplasmic tail were shown to be critical for coupling with G i and SHP-1, 41 respectively. Moreover, the cytoplasmic tail was also shown to contain a binding domain for the transcription factor promyelocytic zinc finger protein (PLZF) which affects the AT2R signaling.…”

mentioning

confidence: 99%

Regulation of Transport of the Angiotensin AT2 Receptor by a Novel Membrane-Associated Golgi Protein

Wruck

Funke-Kaiser

Pufe

et al. 2005

ATVB

124

122

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Objective-Synthesis and maturation of G protein-coupled receptors are complex events that require an intricate combination of processes including protein folding, posttranslational modifications, and transport through distinct cellular compartments. Little is known concerning the regulation of G protein-coupled receptor transport from the endoplasmic reticulum to the cell surface. Methods and Results-Here we show that the cytoplasmatic carboxy-terminal of the angiotensin AT2 receptor (AT2R) acts independently as an endoplasmic reticulum-export signal. Using a yeast two-hybrid system, we identified a Golgi membrane-associated protein termed ATBP50 (for AT2R binding protein of 50 kDa) that binds to this motif. We also cloned ATBP60 and ATBP135 encoded by the same gene as ATBP50 that mapped to chromosomes 8p21.3. Downregulation of ATBP50 using siRNA leads to retention of AT2R in inner compartments, reduced cell surface expression, and decreased antiproliferative effects of the receptor. Conclusion-Our results indicate that ATBP50 regulates the transport of the AT2R to cell membrane by binding to a specific motif within its cytoplasmic carboxy-terminal and thereby enabling the antiproliferative effects of the receptor. T he heptahelical G protein-coupled receptors (GPCRs) represent one of the largest protein families in eukaryotic cells. 1 A large number of structure-function studies have defined receptor sequences that are essential for ligand binding, G protein coupling, and desensitization. In contrast, little is known concerning the requirements for the transport of these proteins to the plasma membrane. Intracellular accessory proteins can be critical for GPCR biogenesis, including aspects of receptor trafficking. Recent discoveries have identified multiple membrane-associated proteins that dictate the delivery of the receptor to the cell surface. 2 See page 15The octapeptide hormone angiotensin II (Ang II) exerts a wide variety of physiological actions such as vasoconstriction and aldosterone secretion, but it is also involved in pathological mechanisms of atherosclerosis as well as vascular and cardiac growth. Ang II mainly interacts with two receptor subtypes, designated AT1 and AT2 receptor (AT1R, AT2R), both belonging to the superfamily of GPCRs. The majority of its well-described effects are mediated by the AT1R. 3 Increasing evidence indicates, however, that the AT2R subtype can modulate the effects of AT1R, including those on blood pressure, 4 -8 cardiac and vascular cell growth, 9 -11 and tissue regeneration after injury. [12][13][14][15] Thus, it has been shown that stimulation or overexpression of AT2R in certain cell lines inhibits cell proliferation induced by growth factors 16,17 and promotes neuronal differentiation 18 -21 as well as apoptosis. [22][23][24][25] The growth inhibitory effects of the AT2R have been shown to be associated with the activation and/or induction of a series of phosphatases including the protein tyrosine phosphatase SHP-1, mitogenactivated protein kinase phosphatase-1 (MK...

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mentioning

confidence: 99%

Regulation of Transport of the Angiotensin AT2 Receptor by a Novel Membrane-Associated Golgi Protein

Wruck

Funke-Kaiser

Pufe

et al. 2005

ATVB

124

122

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“…Mutations of this amino acid are known to affect ligand binding [42]. AT2 does not have an aromatic amino acid at 724, which is required for interaction with the C-terminus of Ang II in AT1 [31].…”

Section: Discussionmentioning

confidence: 99%

Differential Mechanisms of Activation of the Ang Peptide Receptors AT1, AT2, and MAS: Using In Silico Techniques to Differentiate the Three Receptors

2013

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The renin-angiotensin system is involved in multiple conditions ranging from cardiovascular disorders to cancer. Components of the pathway, including ACE, renin and angiotensin receptors are targets for disease treatment. This study addresses three receptors of the pathway: AT1, AT2, and MAS and how the receptors are similar and differ in activation by angiotensin peptides. Combining biochemical and amino acid variation data with multiple species sequence alignments, structural models, and docking site predictions allows for visualization of how angiotensin peptides may bind and activate the receptors; allowing identification of conserved and variant mechanisms in the receptors. MAS differs from AT1 favoring Ang-(1–7) and not Ang II binding, while AT2 recently has been suggested to preferentially bind Ang III. A new model of Ang peptide binding to AT1 and AT2 is proposed that correlates data from site directed mutagenesis and photolabled experiments that were previously considered conflicting. Ang II binds AT1 and AT2 through a conserved initial binding mode involving amino acids 111 (consensus 325) of AT1 (Asn) interacting with Tyr (4) of Ang II and 199 and 256 (consensus 512 and 621, a Lys and His respectively) interacting with Phe (8) of Ang II. In MAS these sites are not conserved, leading to differential binding and activation by Ang-(1–7). In both AT1 and AT2, the Ang II peptide may internalize through Phe (8) of Ang II propagating through the receptors’ conserved aromatic amino acids to the final photolabled positioning relative to either AT1 (amino acid 294, Asn, consensus 725) or AT2 (138, Leu, consensus 336). Understanding receptor activation provides valuable information for drug design and identification of other receptors that can potentially bind Ang peptides.

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“…1, some receptor residues in the TM region and extracellular loops, namely Met 128 and Met 138 [31], Arg 182 [24,25], Lys 215 [26,27], His 273 [28], Asp 279 [30], and Asp 297 [25,29], were suggested to participate in Ang II-AT 2 receptor interactions. The 1327 ligand-receptor configurations were analyzed by measuring the distance between the suggested ligand-receptor contact points.…”

Section: Docking Of the Ang II Model Peptide To The Refined At 2 Recementioning

confidence: 99%

“…Arg 182 [24,25], Lys 215 [26,27], His 273 [28], Asp 297 [25,29], and Asp 279 [30], have been shown to affect affinity of Ang II and Ang II analogues to the AT 2 receptor (for easier notation we herein refer to non-numbered amino acids as part of ligands and numbered amino acids as part of the AT 2 receptor). Notably, the site-directed mutagenesis studies performed for the AT 2 receptor were mainly limited to positions occupied by important residues in the homologous AT 1 receptor.…”

Section: Introductionmentioning

confidence: 99%

Modeling binding modes of angiotensin II and pseudopeptide analogues to the AT2 receptor

Sköld

Nikiforovich

Karlén

2008

Journal of Molecular Graphics and Modelling

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Role of the His273 Located in the Sixth Transmembrane Domain of the Angiotensin II Receptor Subtype AT2 in Ligand–Receptor Interaction

Cited by 17 publications

References 32 publications

Regulation of Transport of the Angiotensin AT2 Receptor by a Novel Membrane-Associated Golgi Protein

Regulation of Transport of the Angiotensin AT2 Receptor by a Novel Membrane-Associated Golgi Protein

Differential Mechanisms of Activation of the Ang Peptide Receptors AT1, AT2, and MAS: Using In Silico Techniques to Differentiate the Three Receptors

Modeling binding modes of angiotensin II and pseudopeptide analogues to the AT2 receptor

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