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The adhesion GPCRs CELSR1–3 and LPHN3 engage G proteins via distinct activation mechanisms

Adhesion G protein-coupled receptors (aGPCRs) are a large GPCR class that direct diverse fundamental biological processes. One prominent mechanism for aGPCR agonism involves autoproteolytic cleavage, which generates an activating, membrane-proximal tethered agonist (TA). How universal this mechanism...

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Autores principales: Bui, Duy Lan Huong, Roach, Andrew, Li, Jingxian, Bandekar, Sumit J., Orput, Elizabeth, Raghavan, Ritika, Araç, Demet, Sando, Richard C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10592476/
https://www.ncbi.nlm.nih.gov/pubmed/37224017
http://dx.doi.org/10.1016/j.celrep.2023.112552
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author Bui, Duy Lan Huong
Roach, Andrew
Li, Jingxian
Bandekar, Sumit J.
Orput, Elizabeth
Raghavan, Ritika
Araç, Demet
Sando, Richard C.
author_facet Bui, Duy Lan Huong
Roach, Andrew
Li, Jingxian
Bandekar, Sumit J.
Orput, Elizabeth
Raghavan, Ritika
Araç, Demet
Sando, Richard C.
author_sort Bui, Duy Lan Huong
collection PubMed
description Adhesion G protein-coupled receptors (aGPCRs) are a large GPCR class that direct diverse fundamental biological processes. One prominent mechanism for aGPCR agonism involves autoproteolytic cleavage, which generates an activating, membrane-proximal tethered agonist (TA). How universal this mechanism is for all aGPCRs is unclear. Here, we investigate G protein induction principles of aGPCRs using mammalian latrophilin 3 (LPHN3) and cadherin EGF LAG-repeat 7-transmembrane receptors 1–3 (CELSR1–3), members of two aGPCR families conserved from invertebrates to vertebrates. LPHNs and CELSRs mediate fundamental aspects of brain development, yet CELSR signaling mechanisms are unknown. We find that CELSR1 and CELSR3 are cleavage deficient, while CELSR2 is efficiently cleaved. Despite differential autoproteolysis, CELSR1–3 all engage GαS, and CELSR1 or CELSR3 TA point mutants retain GαS coupling activity. CELSR2 autoproteolysis enhances GαS coupling, yet acute TA exposure alone is insufficient. These studies support that aGPCRs signal via multiple paradigms and provide insights into CELSR biological function.
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spelling pubmed-105924762023-10-23 The adhesion GPCRs CELSR1–3 and LPHN3 engage G proteins via distinct activation mechanisms Bui, Duy Lan Huong Roach, Andrew Li, Jingxian Bandekar, Sumit J. Orput, Elizabeth Raghavan, Ritika Araç, Demet Sando, Richard C. Cell Rep Article Adhesion G protein-coupled receptors (aGPCRs) are a large GPCR class that direct diverse fundamental biological processes. One prominent mechanism for aGPCR agonism involves autoproteolytic cleavage, which generates an activating, membrane-proximal tethered agonist (TA). How universal this mechanism is for all aGPCRs is unclear. Here, we investigate G protein induction principles of aGPCRs using mammalian latrophilin 3 (LPHN3) and cadherin EGF LAG-repeat 7-transmembrane receptors 1–3 (CELSR1–3), members of two aGPCR families conserved from invertebrates to vertebrates. LPHNs and CELSRs mediate fundamental aspects of brain development, yet CELSR signaling mechanisms are unknown. We find that CELSR1 and CELSR3 are cleavage deficient, while CELSR2 is efficiently cleaved. Despite differential autoproteolysis, CELSR1–3 all engage GαS, and CELSR1 or CELSR3 TA point mutants retain GαS coupling activity. CELSR2 autoproteolysis enhances GαS coupling, yet acute TA exposure alone is insufficient. These studies support that aGPCRs signal via multiple paradigms and provide insights into CELSR biological function. 2023-06-27 2023-05-23 /pmc/articles/PMC10592476/ /pubmed/37224017 http://dx.doi.org/10.1016/j.celrep.2023.112552 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) ).
spellingShingle Article
Bui, Duy Lan Huong
Roach, Andrew
Li, Jingxian
Bandekar, Sumit J.
Orput, Elizabeth
Raghavan, Ritika
Araç, Demet
Sando, Richard C.
The adhesion GPCRs CELSR1–3 and LPHN3 engage G proteins via distinct activation mechanisms
title The adhesion GPCRs CELSR1–3 and LPHN3 engage G proteins via distinct activation mechanisms
title_full The adhesion GPCRs CELSR1–3 and LPHN3 engage G proteins via distinct activation mechanisms
title_fullStr The adhesion GPCRs CELSR1–3 and LPHN3 engage G proteins via distinct activation mechanisms
title_full_unstemmed The adhesion GPCRs CELSR1–3 and LPHN3 engage G proteins via distinct activation mechanisms
title_short The adhesion GPCRs CELSR1–3 and LPHN3 engage G proteins via distinct activation mechanisms
title_sort adhesion gpcrs celsr1–3 and lphn3 engage g proteins via distinct activation mechanisms
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10592476/
https://www.ncbi.nlm.nih.gov/pubmed/37224017
http://dx.doi.org/10.1016/j.celrep.2023.112552
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