G protein-coupled receptors (GPCRs) serve as critical communication hubs, translating a wide range of extracellular signals into intracellular responses that govern numerous physiological processes. In class-A GPCRs, conserved motifs mediate conformational changes of the active states of the receptor, and signal transduction is achieved by selectively binding to Gα proteins and/or adapter protein, arrestin. Apelin receptor (APJR) is a class-A GPCR that regulates a wide range of intracellular signalling cascades in response to apelin and elabela peptide ligands. Understanding how conserved motifs within APJR mediate activation and signal specificity remains unexplored. This study focuses on the functional roles of the DRY and NPxxY motifs within APJR by analyzing their impact on downstream signaling pathways across the receptor's conformational ensembles. Our findings provide compelling evidence that mutations within the conserved DRY and NPxxY motifs of APJR significantly alter its conformational preferences where modification of DRY motif leads to abrogation of G-protein coupling and mutation of NPxxY motif causing abolition of β-arrestin-2 recruitment. These observations shed light on the importance of these motifs in APJR activation and its potential for functional selectivity, highlighting the role of DRY/NPxxY as conformational switches of APJR signalling.
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The cover of this issue of the Biochemical Journal features confocal imaging of internalisation of the APJR-EGFP receptor transiently expressed in HEK293T cells, read more in "Divergent roles of DRY and NPxxY motifs in selective activation of downstream signalling by the apelin receptor" by Aradhyam and colleagues on pages 1707–1722.
Research Article|
November 21 2024
Divergent roles of DRY and NPxxY motifs in selective activation of downstream signalling by the apelin receptor
Subhashree Murali;
Subhashree Murali
Conceptualization, Investigation, Methodology, Writing - original draft
Department of Biotechnology, Bhupat and Jyoti Mehta School of Biological Sciences, Indian Institute of Technology Madras, Chennai, India
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Gopala Krishna Aradhyam
Conceptualization, Resources, Supervision, Funding acquisition, Methodology, Writing - original draft, Writing - review & editing
Department of Biotechnology, Bhupat and Jyoti Mehta School of Biological Sciences, Indian Institute of Technology Madras, Chennai, India
Correspondence: Gopala Krishna Aradhyam ([email protected])
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Publisher: Portland Press Ltd
Received:
June 24 2024
Revision Received:
October 24 2024
Accepted:
November 08 2024
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© 2024 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society
2024
Biochem J (2024) 481 (23): 1707–1722.
Article history
Received:
June 24 2024
Revision Received:
October 24 2024
Accepted:
November 08 2024
Citation
Subhashree Murali, Gopala Krishna Aradhyam; Divergent roles of DRY and NPxxY motifs in selective activation of downstream signalling by the apelin receptor. Biochem J 4 December 2024; 481 (23): 1707–1722. doi: https://doi.org/10.1042/BCJ20240320
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