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The Open Question of How GPCRs Interact with GPCR Kinases (GRKs)

G protein-coupled receptors (GPCRs), which regulate a vast number of eukaryotic processes, are desensitized by various mechanisms but, most importantly, by the GPCR kinases (GRKs). Ever since GRKs were first identified, investigators have sought to determine which structural features of GRKs are use...

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Autores principales: Cato, M. Claire, Yen, Yu-Chen, Francis, Charnelle J., Elkins, Kaely E., Shareef, Afzaal, Sterne-Marr, Rachel, Tesmer, John J. G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002388/
https://www.ncbi.nlm.nih.gov/pubmed/33802765
http://dx.doi.org/10.3390/biom11030447
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author Cato, M. Claire
Yen, Yu-Chen
Francis, Charnelle J.
Elkins, Kaely E.
Shareef, Afzaal
Sterne-Marr, Rachel
Tesmer, John J. G.
author_facet Cato, M. Claire
Yen, Yu-Chen
Francis, Charnelle J.
Elkins, Kaely E.
Shareef, Afzaal
Sterne-Marr, Rachel
Tesmer, John J. G.
author_sort Cato, M. Claire
collection PubMed
description G protein-coupled receptors (GPCRs), which regulate a vast number of eukaryotic processes, are desensitized by various mechanisms but, most importantly, by the GPCR kinases (GRKs). Ever since GRKs were first identified, investigators have sought to determine which structural features of GRKs are used to select for the agonist-bound states of GPCRs and how this binding event in turn enhances GRK catalytic activity. Despite a wealth of molecular information from high-resolution crystal structures of GRKs, the mechanisms driving activation have remained elusive, in part because the GRK N-terminus and active site tether region, previously proposed to serve as a receptor docking site and to be key to kinase domain closure, are often disordered or adopt inconsistent conformations. However, two recent studies have implicated other regions of GRKs as being involved in direct interactions with active GPCRs. Atomic resolution structures of GPCR–GRK complexes would help refine these models but are, so far, lacking. Here, we assess three distinct models for how GRKs recognize activated GPCRs, discuss limitations in the approaches used to generate them, and then experimentally test a hypothetical GPCR interaction site in GRK2 suggested by the two newest models.
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spelling pubmed-80023882021-03-28 The Open Question of How GPCRs Interact with GPCR Kinases (GRKs) Cato, M. Claire Yen, Yu-Chen Francis, Charnelle J. Elkins, Kaely E. Shareef, Afzaal Sterne-Marr, Rachel Tesmer, John J. G. Biomolecules Article G protein-coupled receptors (GPCRs), which regulate a vast number of eukaryotic processes, are desensitized by various mechanisms but, most importantly, by the GPCR kinases (GRKs). Ever since GRKs were first identified, investigators have sought to determine which structural features of GRKs are used to select for the agonist-bound states of GPCRs and how this binding event in turn enhances GRK catalytic activity. Despite a wealth of molecular information from high-resolution crystal structures of GRKs, the mechanisms driving activation have remained elusive, in part because the GRK N-terminus and active site tether region, previously proposed to serve as a receptor docking site and to be key to kinase domain closure, are often disordered or adopt inconsistent conformations. However, two recent studies have implicated other regions of GRKs as being involved in direct interactions with active GPCRs. Atomic resolution structures of GPCR–GRK complexes would help refine these models but are, so far, lacking. Here, we assess three distinct models for how GRKs recognize activated GPCRs, discuss limitations in the approaches used to generate them, and then experimentally test a hypothetical GPCR interaction site in GRK2 suggested by the two newest models. MDPI 2021-03-17 /pmc/articles/PMC8002388/ /pubmed/33802765 http://dx.doi.org/10.3390/biom11030447 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ).
spellingShingle Article
Cato, M. Claire
Yen, Yu-Chen
Francis, Charnelle J.
Elkins, Kaely E.
Shareef, Afzaal
Sterne-Marr, Rachel
Tesmer, John J. G.
The Open Question of How GPCRs Interact with GPCR Kinases (GRKs)
title The Open Question of How GPCRs Interact with GPCR Kinases (GRKs)
title_full The Open Question of How GPCRs Interact with GPCR Kinases (GRKs)
title_fullStr The Open Question of How GPCRs Interact with GPCR Kinases (GRKs)
title_full_unstemmed The Open Question of How GPCRs Interact with GPCR Kinases (GRKs)
title_short The Open Question of How GPCRs Interact with GPCR Kinases (GRKs)
title_sort open question of how gpcrs interact with gpcr kinases (grks)
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002388/
https://www.ncbi.nlm.nih.gov/pubmed/33802765
http://dx.doi.org/10.3390/biom11030447
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