Mutation of Tyrosine in the Conserved NPXXY Sequence Leads to Constitutive Phosphorylation and Internalization, but Not Signaling, of the Human B2 Bradykinin Receptor
Although the G protein-coupled receptors (GPCRs) share a similar seven-transmembrane domain structure, only a limited number of amino acid residues is conserved in their protein sequences. One of the most highly conserved sequences is the NP XX Y motif located at the cytosolic end of the transmembra...
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Published in | The Journal of biological chemistry Vol. 279; no. 30; pp. 31268 - 31276 |
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Main Authors | , , , , , , |
Format | Journal Article |
Language | English |
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American Society for Biochemistry and Molecular Biology
23.07.2004
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Abstract | Although the G protein-coupled receptors (GPCRs) share a similar seven-transmembrane domain structure, only a limited number
of amino acid residues is conserved in their protein sequences. One of the most highly conserved sequences is the NP XX Y motif located at the cytosolic end of the transmembrane region-7 of many GPCRs, particularly of those belonging to the family
of the rhodopsin/β-adrenergic-like receptors. Exchange of Tyr 305 in the corresponding NPLVY sequence of the bradykinin B 2 receptor (B 2 R) for Ala resulted in a mutant, termed Y305A, that internalized [ 3 H]bradykinin (BK) almost as rapidly as the wild-type (wt) B 2 R. However, receptor sequestration of the mutant after stimulation with BK was clearly reduced relative to the wt B 2 R. Confocal fluorescence microscopy revealed that, in contrast to the B 2 R-enhanced green fluorescent protein chimera, the Y305A-enhanced green fluorescent protein chimera was predominantly located
intracellularly even in the absence of BK. Two-dimensional phosphopeptide analysis showed that the mutant Y305A constitutively
exhibited a phosphorylation pattern similar to that of the BK-stimulated wt B 2 R. Ligand-independent Y305A internalization was demonstrated by the uptake of rhodamine-labeled antibodies directed to a tag
sequence at the N terminus of the mutant receptor. Co-immunoprecipitation revealed that Y305A is precoupled to G q/11 without activating the G protein because the basal accumulation rate of inositol phosphate was unchanged as compared with
wt B 2 R. We conclude, therefore, that the Y305A mutation of B 2 R induces a receptor conformation which is prone to ligand-independent phosphorylation and internalization. The mutated receptor
binds to, but does not activate, its cognate heterotrimeric G protein G q/11 , thereby limiting the extent of ligand-independent receptor internalization. |
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AbstractList | Although the G protein-coupled receptors (GPCRs) share a similar seven-transmembrane domain structure, only a limited number of amino acid residues is conserved in their protein sequences. One of the most highly conserved sequences is the NPXXY motif located at the cytosolic end of the transmembrane region-7 of many GPCRs, particularly of those belonging to the family of the rhodopsin/beta-adrenergic-like receptors. Exchange of Tyr(305) in the corresponding NPLVY sequence of the bradykinin B(2) receptor (B(2)R) for Ala resulted in a mutant, termed Y305A, that internalized [(3)H]bradykinin (BK) almost as rapidly as the wild-type (wt) B(2)R. However, receptor sequestration of the mutant after stimulation with BK was clearly reduced relative to the wt B(2)R. Confocal fluorescence microscopy revealed that, in contrast to the B(2)R-enhanced green fluorescent protein chimera, the Y305A-enhanced green fluorescent protein chimera was predominantly located intracellularly even in the absence of BK. Two-dimensional phosphopeptide analysis showed that the mutant Y305A constitutively exhibited a phosphorylation pattern similar to that of the BK-stimulated wt B(2)R. Ligand-independent Y305A internalization was demonstrated by the uptake of rhodamine-labeled antibodies directed to a tag sequence at the N terminus of the mutant receptor. Co-immunoprecipitation revealed that Y305A is precoupled to G(q/11) without activating the G protein because the basal accumulation rate of inositol phosphate was unchanged as compared with wt B(2)R. We conclude, therefore, that the Y305A mutation of B(2)R induces a receptor conformation which is prone to ligand-independent phosphorylation and internalization. The mutated receptor binds to, but does not activate, its cognate heterotrimeric G protein G(q/11), thereby limiting the extent of ligand-independent receptor internalization. Although the G protein-coupled receptors (GPCRs) share a similar seven-transmembrane domain structure, only a limited number of amino acid residues is conserved in their protein sequences. One of the most highly conserved sequences is the NP XX Y motif located at the cytosolic end of the transmembrane region-7 of many GPCRs, particularly of those belonging to the family of the rhodopsin/β-adrenergic-like receptors. Exchange of Tyr 305 in the corresponding NPLVY sequence of the bradykinin B 2 receptor (B 2 R) for Ala resulted in a mutant, termed Y305A, that internalized [ 3 H]bradykinin (BK) almost as rapidly as the wild-type (wt) B 2 R. However, receptor sequestration of the mutant after stimulation with BK was clearly reduced relative to the wt B 2 R. Confocal fluorescence microscopy revealed that, in contrast to the B 2 R-enhanced green fluorescent protein chimera, the Y305A-enhanced green fluorescent protein chimera was predominantly located intracellularly even in the absence of BK. Two-dimensional phosphopeptide analysis showed that the mutant Y305A constitutively exhibited a phosphorylation pattern similar to that of the BK-stimulated wt B 2 R. Ligand-independent Y305A internalization was demonstrated by the uptake of rhodamine-labeled antibodies directed to a tag sequence at the N terminus of the mutant receptor. Co-immunoprecipitation revealed that Y305A is precoupled to G q/11 without activating the G protein because the basal accumulation rate of inositol phosphate was unchanged as compared with wt B 2 R. We conclude, therefore, that the Y305A mutation of B 2 R induces a receptor conformation which is prone to ligand-independent phosphorylation and internalization. The mutated receptor binds to, but does not activate, its cognate heterotrimeric G protein G q/11 , thereby limiting the extent of ligand-independent receptor internalization. |
Author | David Proud Andree Blaukat Marianne Jochum Steffen Schüssler Alexander Faussner Irina Kalatskaya Werner Müller-Esterl |
Author_xml | – sequence: 1 givenname: Irina surname: Kalatskaya fullname: Kalatskaya, Irina organization: Abteilung für Klinische Chemie und Klinische Biochemie, Ludwig-Maximilians-Universität, Nussbaumstrasse 20, D-80336 München, Germany – sequence: 2 givenname: Steffen surname: Schüssler fullname: Schüssler, Steffen – sequence: 3 givenname: Andree surname: Blaukat fullname: Blaukat, Andree – sequence: 4 givenname: Werner surname: Müller-Esterl fullname: Müller-Esterl, Werner – sequence: 5 givenname: Marianne surname: Jochum fullname: Jochum, Marianne – sequence: 6 givenname: David surname: Proud fullname: Proud, David – sequence: 7 givenname: Alexander surname: Faussner fullname: Faussner, Alexander |
BackLink | https://www.ncbi.nlm.nih.gov/pubmed/15161928$$D View this record in MEDLINE/PubMed |
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Snippet | Although the G protein-coupled receptors (GPCRs) share a similar seven-transmembrane domain structure, only a limited number
of amino acid residues is... Although the G protein-coupled receptors (GPCRs) share a similar seven-transmembrane domain structure, only a limited number of amino acid residues is... |
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StartPage | 31268 |
SubjectTerms | Amino Acid Sequence Cell Line Conserved Sequence GTP-Binding Protein alpha Subunits, Gq-G11 - metabolism Humans In Vitro Techniques Kinetics Ligands Mutagenesis, Site-Directed Phosphorylation Protein Conformation Receptor, Bradykinin B2 - chemistry Receptor, Bradykinin B2 - genetics Receptor, Bradykinin B2 - metabolism Recombinant Fusion Proteins - chemistry Recombinant Fusion Proteins - genetics Recombinant Fusion Proteins - metabolism Signal Transduction Tyrosine - chemistry Tyrosine - genetics |
Title | Mutation of Tyrosine in the Conserved NPXXY Sequence Leads to Constitutive Phosphorylation and Internalization, but Not Signaling, of the Human B2 Bradykinin Receptor |
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